Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use

ABSTRACT

Indazole compounds that modulate and/or inhibit the activity of certain protein kinases are described. These compounds and pharmaceutical compositions containing them are capable of mediating tyrosine kinase signal transduction and thereby modulate and/or inhibit unwanted cell proliferation. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds, and to methods of treating cancer and other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis, by administering effective amounts of such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional PatentApplication No. 60/142,130, filed Jul. 2, 1999.

FIELD OF THE INVENTION

[0002] This invention is directed to indazole compounds that mediateand/or inhibit the activity of certain protein kinases, and topharmaceutical compositions containing such compounds. The invention isalso directed to the therapeutic or prophylactic use of such compoundsand compositions, and to methods of treating cancer as well as otherdisease states associated with unwanted angiogenesis and/or cellularproliferation, by administering effective amounts of such compounds.

BACKGROUND OF THE INVENTION

[0003] Protein kinases are a family of enzymes that catalyzephosphorylation of the hydroxyl group of specific tyrosine, serine, orthreonine residues in proteins. Typically, such phosphorylationdramatically perturbs the function of the protein, and thus proteinkinases are pivotal in the regulation of a wide variety of cellularprocesses, including metabolisim, cell proliferation, celldifferentiation, and cell survival. Of the many different cellularfunctions in which the activity of protein kinases is known to berequired, some processes represent attractive targets for therapeuticintervention for certain disease states. Two examples are angiogenesisand cell-cycle control, in which protein kinases play a pivotal role;these processes are essential for the growth of solid tumors as well asfor other diseases.

[0004] Angiogenesis is the mechanism by which new capillaries are formedfrom existing vessels. When required, the vascular system has thepotential to generate new capillary networks in order to maintain theproper functioning of tissues and organs. In the adult, however,angiogenesis is fairly limited, occurring only in the process of woundhealing and neovascularization of the endometrium during menstruation.See Merenmies et al., Cell Growth & Differentiation, 8, 3-10 (1997). Onthe other hand, unwanted angiogenesis is a hallmark of several diseases,such as retinopathies, psoriasis, rheumatoid arthritis, age-relatedmacular degeneration (AMD), and cancer (solid tumors). Folkman, NatureMed., 1, 27-31 (1995). Protein kinases which have been shown to beinvolved in the angiogenic process include three members of the growthfactor receptor tyrosine kinase family: VEGF-R2 (vascular endothelialgrowth factor receptor 2, also known as KDR (kinase insert domainreceptor) and as FLK-1); FGF-R (fibroblast growth factor receptor); andTEK (also known as Tie-2).

[0005] VEGF-R2, which is expressed only on endothelial cells, binds thepotent angiogenic growth factor VEGF and mediates the subsequent signaltransduction through activation of its intracellular kinase activity.Thus, it is expected that direct inhibition of the kinase activity ofVEGF-R2 will result in the reduction of angiogenesis even in thepresence of exogenous VEGF (see Strawn et al., Cancer Research, 56,3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which failto mediate signal transduction. Millauer et al., Cancer Research, 56,1615-1620 (1996). Furthermore, VEGF-R2 appears to have no function inthe adult beyond that of mediating the angiogenic activity of VEGF.Therefore, a selective inhibitor of the kinase activity of VEGF-R2 wouldbe expected to exhibit little toxicity.

[0006] Similarly, FGF-R binds the angiogenic growth factors aFGF andbFGF and mediates subsequent intracellular signal transduction.Recently, it has been suggested that growth factors such as bFGF mayplay a critical role in inducing angiogenesis in solid tumors that havereached a certain size. Yoshiji et al., Cancer Research, 57, 3924-3928(1997). Unlike VEGF-R2, however, FGF-R is expressed in a number ofdifferent cell types throughout the body and may or may not playimportant roles in other normal physiological processes in the adult.Nonetheless, systemic administration of a small-molecule inhibitor ofthe kinase activity of FGF-R has been reported to block bFGF-inducedangiogenesis in mice without apparent toxicity. Mohammad et al., EMBOJournal, 17, 5996-5904 (1998).

[0007] TEK (also known as Tie-2) is another receptor tyrosine kinaseexpressed only on endothelial cells which has been shown to play a rolein angiogenesis. The binding of the factor angiopoietin-1 results inautophosphorylation of the kinase domain of TEK and results in a signaltransduction process which appears to mediate the interaction ofendothelial cells with peri-endothelial support cells, therebyfacilitating the maturation of newly formed blood vessels. The factorangiopoietin-2, on the other hand, appears to antagonize the action ofangiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al.,Science, 277, 55-60 (1997).

[0008] As a result of the above-described developments, it has beenproposed to treat angiogenesis by the use of compounds inhibiting thekinase activity of VEGF-R2, FGF-R, and/or TEK. For example, WIPOInternational Publication No. WO 97/34876 discloses certain cinnolinederivatives that are inhibitors of VEGF-R2, which may be used for thetreatment of disease states associated with abnormal angiogenesis and/orincreased vascular permeability such as cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restinosis, autoimmune diseases, acuteinflammation, and ocular diseases with retinal vessel proliferation.

[0009] Phosphorylase kinase activates glycogen phosphorylase, thusincreasing glycogen breakdown and hepatic glucose release. Hepaticglucose production is disregulated in type 2 diabetes, and is theprimary cause of fasting hyperglycemia, which results in many of thesecondary complications afflicting these patients. Thus, reduction inglucose release from the liver would lower elevated plasma glucoselevels. Inhibitors of phosphorylase kinase should therefore decreasephosphorylase activity and glycogenolysis, thus reducing hyperglycemiain patients.

[0010] Another physiological response to VEGF is vascularhyperpermeability, which has been proposed to play a role in the earlystages of angiogenesis. In ischemic tissues, such as those occurring inthe brain of stroke victims, hypoxia trigger VEGF expression, leading toincreased vascular permeability and ultimately edema in the surroundingtissues. In a rat model for stroke, it has been shown by van Bruggen etal., J. Clinical Invest., 104, 1613-20 (1999) that administration of amonoclonal antibody to VEGF reduces the infarct volume. Thus, inhibitorsof VEGFR are anticipated to be useful for the treatment of stroke.

[0011] In addition to its role in angiogenesis, protein kinases alsoplay a crucial role in cell-cycle control. Uncontrolled cellproliferation is the insignia of cancer. Cell proliferation in responseto various stimuli is manifested by a de-regulation of the cell divisioncycle, the process by which cells multiply and divide. Tumor cellstypically have damage to the genes that directly or indirectly regulateprogression through the cell division cycle.

[0012] Cyclin-dependent kinases (CDKs) are serine-threonine proteinkinases that play critical roles in regulating the transitions betweendifferent phases of the cell cycle. See, e.g., the articles compiled inScience, 274, 1643-1677 (1996). CDK complexes are formed throughassociation of a regulatory cyclin subunit (e.g., cyclin A, B1, B2, D1,D2, D3, and E) and a catalytic kinase subunit (e.g., cdc2 (CDK1), CDK2,CDK4, CDK5, and CDK6). As the name implies, the CDKs display an absolutedependence on the cyclin subunit in order to phosphorylate their targetsubstrates, and different kinase/cyclin pairs function to regulateprogression through specific phases of the cell cycle.

[0013] It is CDK4 complexed to the D cyclins that plays a critical partin initiating the cell-division cycle from a resting or quiescent stageto one in which cells become committed to cell division. Thisprogression is subject to a variety of growth regulatory mechanisms,both negative and positive. Aberrations in this control system,particularly those that affect the function of CDK4, have beenimplicated in the advancement of cells to the highly proliferative statecharacteristic of malignancies, particularly familial melanomas,esophageal carcinomas, and pancreatic cancers. See, e.g., Karnb, Trendsin Genetics, 11, 136-140 (1995); Kamb et al., Science, 264, 436-440(1994).

[0014] Myriad publications describe a variety of chemical compoundsuseful against a variety of therapeutic targets. For example, WIPOInternational Publication Nos. WO 99/23077 and WO 99/23076 describeindazole-containing compounds having phosphodiesterase type IVinhibitory activity produced by an indazole-for-catechol bioisosterereplacement. U.S. Pat. No. 5,760,028 discloses heterocycles including3-[1-[3-(imidazolin-2-ylamino)propyl]indazol-5-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid, which are useful as antagonists of the α_(v)β₃ integrin andrelated cell surface adhesive protein receptors. WIPO InternationalPublication No. WO 98/09961 discloses certain indazole derivatives andtheir use as inhibitors of phosphodiesterase (PDE) type IV or theproduction of tumor necrosis factor (TNF) in a mammal. Recent additionsto the virtual library of known compounds include those described asbeing anti-proliferative therapeutic agents that inhibit CDKs. Forexample, U.S. Pat. No. 5,621,082 to Xiong et al. discloses nucleic acidencoding an inhibitor of CDK6, and European Patent Publication No. 0 666270 A2 describes peptides and peptide mimetics that act as inhibitors ofCDK1 arid CDK2. WIPO International Publication No. WO 97/16447 disclosescertain analogs of chromones that are inhibitors of cyclin-dependentkinases, in particular of CDK/cyclin complexes such as CDK4/cyclin D1,which may be used for inhibiting excessive or abnormal cellproliferation, and therefore for treating cancer. WIPO InternationalPublication No. WO 99/21845 describes 4-aminothiazole derivatives thatare useful as CDK inhibitors.

[0015] There is still a need, however, for small-molecule compounds thatmay be readily synthesized and are effective in inhibiting one or moreCDKs or CDK/cyclin complexes. Because CDK4 may serve as a generalactivator of cell division in most cells, and complexes of CDK4 andD-type cyclins govern the early G₁ phase of the cell cycle, there is aneed for effective inhibitors of CDK4, and D-type cyclin complexesthereof, for treating one or more types of tumors. Also, the pivotalroles of cyclin E/CDK2 and cyclin B/CDK1 kinases in the G₁/S phase andG₂/M transitions, respectively, offer additional targets for therapeuticintervention in suppressing deregulated cell-cycle progression incancer.

[0016] Another protein kinase, CHK1, plays an important role as acheckpoint in cell-cycle progression. Checkpoints are control systemsthat coordinate cell-cycle progression by influencing the formation,activation and subsequent inactivation of the cyclin-dependent kinases.Checkpoints prevent cell-cycle progression at inappropriate times,maintain the metabolic balance of cells while the cell is arrested, andin some instances can induce apoptosis (programmed cell death) when therequirements of the checkpoint have not been met. See, e.g., O'Connor,Cancer Surveys, 29, 151-182 (1997); Nurse, Cell, 91, 865-867 (1997);Hartwell et al., Science, 266, 1821-1828 (1994); Hartwell et al.,Science, 246, 629-634 (1989).

[0017] One series of checkpoints monitors the integrity of the genomeand, upon sensing DNA damage, these “DNA damage checkpoints” blockcell-cycle progression in G₁ and G₂ phases, and slow progression throughS phase. O'Connor, Cancer Surveys, 29, 151-182 (1997); Hartwell et al.,Science, 266, 1821-1828 (1994). This action enables DNA repair processesto complete their tasks before replication of the genome and subsequentseparation of this genetic material into new daughter cells takes place.Importantly, the most commonly mutated gene in human cancer, the p53tumor suppressor gene, produces a DNA damage checkpoint protein thatblocks cell-cycle progression in G₁ phase and/or induces apoptosis(programmed cell death) following DNA damage. Hartwell et al., Science,266, 1821-1828 (1994). The p53 tumor suppressor has also been shown tostrengthen the action of a DNA damage checkpoint in G₂ phase of the cellcycle. See, e.g., Bunz et al., Science, 28, 1497-1501 (1998); Winters etal., Oncogene, 17, 673-684 (1998); Thompson, Oncogene, 15, 3025-3035(1997).

[0018] Given the pivotal nature of the p53 tumor suppressor pathway inhuman cancer, therapeutic interventions that exploit vulnerabilities inp53-defective cancer have been actively sought. One emergingvulnerability lies in the operation of the G₂ checkpoint in p53defective cancer cells. Cancer cells, because they lack G₁ checkpointcontrol, are particularly vulnerable to abrogation of the last remainingbarrier protecting them from the cancer-killing effects of DNA-damagingagents: the G₂ checkpoint. The G₂ checkpoint is regulated by a controlsystem that has been conserved from yeast to humans. Important in thisconserved system is a kinase, CHK1, which transduces signals from theDNA-damage sensory complex to inhibit activation of the cyclin B/Cdc2kinase, which promotes mitotic entry. See, e.g., Peng et al., Science,277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997).Inactivation of CHK1 has been shown to both abrogate G₂ arrest inducedby DNA damage inflicted by either anticancer agents or endogenous DNAdamage, as well as result in preferential killing of the resultingcheckpoint defective cells. See, e.g., Nurse, Cell, 91, 865-867 (1997);Weinert, Science, 277, 1450-1451 (1997); Walworth et al., Nature, 363,368-371 (1993); and Al-Khodairy et al., Molec. BioL Cell, 5, 147-160(1994).

[0019] Selective manipulation of checkpoint control in cancer cellscould afford broad utilization in cancer chemotherapeutic andradiotherapy regimens and may, in addition, offer a common hallmark ofhuman cancer “genomic instability” to be exploited as the selectivebasis for the destruction of cancer cells. A number of factors placeCHK1 as a pivotal target in DNA-danage checkpoint control. Theelucidation of inhibitors of this and functionally related kinases suchas Cds1/CHK2, a kinase recently discovered to cooperate with CHK1 inregulating S phase progression (see Zeng et al., Nature, 395, 507-510(1998); Matsuoka, Science, 282, 1893-1897 (1998)), could providevaluable new therapeutic entities for the treatment of cancer.

[0020] Integrin receptor binding to ECM initiates intracellular signalsmediated by FAK (Focal Adhesion Kinase) that are involved in cellmotility, cellular proliferation, and survival. In human cancers, FAKoverexpression is implicated in tumorigenesis and metastatic potentialthrough its role in integrin mediated signaling pathways.

[0021] Tyrosine kinases can be of the receptor type (havingextracellular, transmembrane and intracellular domains) or thenon-receptor type (being wholly intracellular). At least one of thenon-receptor protein tyrosine kinases, namely, LCK, is believed tomediate the transduction in T-cells of a signal from the interaction ofa cell-surface protein (Cd4) with a cross-linked anti-Cd4 antibody. Amore detailed discussion of non-receptor tyrosine kinases is provided inBolen, Oncogene, 8, 2025-2031 (1993), which is incorporated herein byreference.

[0022] In addition to the protein kinases identified above, many otherprotein kinases have been considered to be therapeutic targets, andnumerous publications disclose inhibitors of kinase activity, asreviewed in the following: McMahon et al, Oncologist, 5, 3-10 (2000);Holash et al., Oncogene, 18, 5356-62 (1999); Thomas et al., J. Biol.Chem., 274, 36684-92 (1999); Cohen, Curr. Op. Chem. Biol., 3, 459-65(1999); Klohs et al., Curr. Op. Chem. Biol., 10, 544-49 (1999); McMahonet al., Current Opinion in Drug Discovery & Development, 1, 131-146(1998); Strawn et al., Exp. Opin. Invest. Drugs, 7, 553-573 (1998). WIPOInternational Publication WO 00/18761 discloses certain substituted3-cyanoquinolines as protein kinase inhibitors.

[0023] There is still a need, however, for effective inhibitors ofprotein kinases. Moreover, as is understood by those skilled in the art,it is desirable for kinase inhibitors to possess both high affinity forthe target kinase or kinases as well as high selectivity versus otherprotein kinases.

SUMMARY OF THE INVENTION

[0024] Thus, an objective of the invention is to discover potentinhibitors of protein kinases. Another objective of the invention is todiscover effective kinase inhibitors having a strong and selectiveaffinity for one or more particular kinases.

[0025] These and other objectives of the invention, which will becomeapparent from the following description, have been achieved by thediscovery of the indazole compounds, pharmaceutically acceptableprodrugs, pharmaceutically active metabolites, and pharmaceuticallyacceptable salts thereof (such compounds, prodrugs, metabolites andsalts are collectively referred to as “agents”) described below, whichmodulate and/or inhibit the activity of protein kinases. Pharmaceuticalcompositions containing such agents are useful in treating diseasesmediated by kinase activity, such as cancer, as well as other diseasestates associated with unwanted angiogenesis and/or cellularproliferation, such as diabetic retinopathy, neovascular glaucoma,rheumatoid arthritis, and psoriasis. Further, the agents haveadvantageous properties relating to the modulation and/or inhibition ofthe kinase activity associated with VEGF-R, FGF-R, CDK complexes, CHK1,LCK, TEK, FAK, and/or phosphorylase kinase.

[0026] In a general aspect, the invention relates to compounds of theFormula I:

[0027] wherein:

[0028] R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³ where R³ is a substituted orunsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; and

[0029] R² is a substituted or unsubstituted aryl, heteroaryl, or Y-X,where Y is 0, S, C═CH₂, C═O, S═O, SO₂, alkylidene, NH, or N-(C₁-C₈alkyl), and X is substituted or unsubstituted Ar, heteroaryl,NH-(alkyl), NH-(cycloalkyl), NH-(heterocycloalkyl), NH(aryl),NH(heteroaryl), NH-(alkoxyl), or NH-(dialkylamide), where Ar is aryl;

[0030] The invention is also directed to pharmaceutically acceptableprodrugs, pharmaceutically active metabolites, and pharmaceuticallyacceptable salts of the compounds of Formula I. Advantageous methods ofmaking the compounds of the Formula I are also described.

[0031] In another general aspect, the invention relates to compounds ofthe Formula I(a):

[0032] wherein:

[0033] R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³or CH═N—R³ where R³ is a substituted orunsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; and

[0034] R² is a substituted or unsubstituted aryl or Y-Ar, where Y is O,S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₁-C₈ alkyl), and Ar is asubstituted or unsubstituted aryl.

[0035] The invention is also directed to pharmaceutically acceptableprodrugs, pharmaceutically active metabolites, and pharmaceuticallyacceptable salts of the compounds of Formula I(a). Advantageous methodsof making the compounds of the Formula I(a) are also described.

[0036] In one preferred general embodiment, the invention relates tocompounds having the Formula II:

[0037] wherein:

[0038] R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0039] R⁴ and R⁷. are each independently hydrogen, OH, halo, C₁-C₈alkyl, C₁-C₈ alkoxy, C₁-C₈ alkenyl, aryloxy, thioaryl, CH₂—OH, CH₂—O—(C₁-C₈ alkyl), CH₂—O-aryl, CH₂-S-(C₁-C₈ alkyl), or CH₂-S-aryl;

[0040] R⁵ and R⁶ are each independently hydrogen, OH, halo, Z-alkyl,Z-aryl, or Z-CH₂CH═CH₂, where Z is O, S, NH, or CH₂, and the alkyl andaryl moieties of Z-alkyl and Z-aryl are each optionally substituted;

[0041] and pharmaceutically acceptable prodrugs, pharmaceutically activemetabolites, and pharmaceutically acceptable salts thereof.

[0042] In a preferred embodiment of Formula II: R¹ is a substituted orunsubstituted bicyclic heteroaryl, or a group of the formula CH═CH—R³where R³ is a substituted or unsubstituted aryl or heteroaryl; R⁴ and R⁷are each independently hydrogen or C₁-C₈ alkyl; and R⁵ and R⁶ are eachindependently halo, Z-alkyl, or Z-CH₂CH═CH₂, where Z is O or S.

[0043] In another preferred general embodiment, compounds of theinvention are of Formula III:

[0044] wherein:

[0045] R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0046] Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₁-C₈alkyl);

[0047] R⁸ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxyl, or aryloxyl;

[0048] R¹⁰ is independently selected from hydrogen, halogen, andlower-alkyl; and pharmaceutically acceptable prodrugs, pharmaceuticallyacceptable metabolites, and pharmaceutically acceptable salts thereof.

[0049] More preferably, in Formula III: R¹ is a substituted orunsubstituted bicyclic heteroaryl, or a group of the formula CH═CH—R³where R³ is a substituted or unsubstituted aryl or heteroaryl; Y is O,S, C═CH₂, C═O, NH, or N-(C₁-C₈ alkyl); R⁸ is a substituted orunsubstituted aryl, heteroaryl, alkyl, and alkenyl, and R¹⁰ is hydrogenor halogen.

[0050] In another preferred general embodiment, compounds of theinvention are of Formula III(a):

[0051] wherein:

[0052] R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0053] Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₁-C₈alkyl);

[0054] R⁸ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxyl, or aryloxyl;

[0055] and pharmaceutically acceptable prodrugs, pharmaceuticallyacceptable metabolites, and pharmaceutically acceptable salts thereof.

[0056] More preferably, in Formula III(a): R¹ is a substituted orunsubstituted bicyclic heteroaryl, or a group of the formula CH═CH—R3where R³ is a substituted or unsubstituted aryl or heteroaryl; Y is O,S, C═CH₂, C═O, NH, or N-(C₁-C₈ alkyl); and R⁸ is a substituted orunsubstituted aryl or heteroaryl.

[0057] In another preferred general embodiment, compounds of theinvention are of Formula IV:

[0058] wherein:

[0059] R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0060] Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₁-C₈alkyl);

[0061] R⁹ is a substituted or unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl,NH-(C₁-C₈ alkyl), NH-(aryl), NH-(heteroaryl), N═CH-alkyl), NH(C═O)R¹¹,or NH₂, where R¹¹ is independently selected from hydrogen, substitutedor unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl; and

[0062] R¹⁰ is independently selected from hydrogen, halogen, andlower-alkyl;

[0063] and pharmaceutically acceptable prodrugs, pharmaceuticallyacceptable metabolites, and pharmaceutically acceptable salts thereof.

[0064] More preferably, in Formula IV: R¹ is a group of the formulaCH═CH—R³ where R³ is a substituted or unsubstituted aryl or heteroaryl;Y is S or NH, and R⁹ is a substituted or unsubstituted alkyl, alkoxyl,or NH-(heteroaryl).

[0065] Most preferred are compounds of the invention selected from:

[0066] The invention also relates to a method of modulating and/orinhibiting the kinase activity of VEGF-R, FGF-R, a CDK complex, CHK1,LCK, TEK, FAK, and/or phosphorylase kinase by administering a compoundof the Formula I, II, III, or IV, or a pharmaceutically acceptableprodrug, pharmaceutically active metabolite, or pharmaceuticallyacceptable salt thereof. Preferred compounds of the present inventionthat have selective kinase activity—i.e., they possess significantactivity against one or more specific kinases while possessing less orminimal activity against one or more different kinases. In one preferredembodiment of the invention, compounds of the present invention arethose of Formula I possessing substantially higher potency against VEGFreceptor tyrosine kinase than against FGF-R1 receptor tyrosine kinase.The invention is also directed to methods of modulating VEGF receptortyrosine kinase activity without significantly modulating FGF receptortyrosine kinase activity.

[0067] The inventive compounds may be used advantageously in combinationwith other known therapeutic agents. For example, compounds of FormulaI, II, III, or IV which possess antiangiogenic activity may beco-administered with cytotoxic chemotherapeutic agents, such as taxol,taxotere, vinblastine, cis-platin, doxorubicin, adriamycin, and thelike, to produce an enhanced antitumor effect. Additive or synergisticenhancement of therapeutic effect may also be obtained byco-administration of compounds of Formula I, II, III, or IV whichpossess antiangiogenic activity with other antiangiogenic agents, suchas combretastatin A-4, endostatin, prinomastat, celecoxib, rofocoxib,EMD121974, IM862, anti-VEGF monoclonal antibodies, and anti-KDRmonoclonal antibodies.

[0068] The invention also relates pharmaceutical compositions, eachcomprising an effective amount of an agent selected from compounds ofFormula I and pharmaceutically acceptable salts, pharmaceutically activemetabolites, and pharmaceutically acceptable prodrugs thereof; and apharmaceutically acceptable carrier or vehicle for such agent. Theinvention further provides methods of treating cancer as well as otherdisease states associated with unwanted angiogenesis and/or cellularproliferation, comprising administering effective amounts of such anagent to a patient in need of such treatment.

DETAILED DESCRIPTION OF INVENTION AND PREFERRED EMBODIMENTS

[0069] The inventive compounds of the Formula I, II, III, and IV areuseful for mediating the activity of protein kinases. More particularly,the compounds are useful as anti-angiogenesis agents and as agents formodulating and/or inhibiting the activity of protein kinases, thusproviding treatments for cancer or other diseases associated withcellular proliferation mediated by protein kinases.

[0070] The term “alkyl” as used herein refers to straight- andbranched-chain alkyl groups having one to twelve carbon atoms. Exemplaryalkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl,tert-pentyl, hexyl, isohexyl, and the like. The term “lower alkyl”designates an alkyl having from 1 to 8 carbon atoms (a C₁₋₈-alkyl).Suitable substituted alkyls include fluoromethyl, difluoromethyl,trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, and the like.

[0071] The term “alkylidene” refers to a divalent radical having one totwelve carbon atoms. Illustrative alkylidene groups include CH₂, CHCH₃,(CH₃)₂, and the like.

[0072] The term “alkenyl” refers to straight- and branched-chain alkenylgroups having from two to twelve carbon atoms. Illustrative alkenylgroups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl,hex-2-enyl, and the like.

[0073] The term “alkynyl” refers to straight- and branched-chain alkynylgroups having from two to twelve carbon atoms.

[0074] The term “cycloalkyl” refers to saturated or partiallyunsaturated carbocycles having from three to twelve carbon atoms,including bicyclic and tricyclic cycloalkyl structures. Suitablecycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like.

[0075] A “heterocycloalkyl” group is intended to mean a saturated orpartially unsaturated monocyclic radical containing carbon atoms,preferably 4 or 5 ring carbon atoms, and at least one heteroatomselected from nitrogen, oxygen and sulfur.

[0076] The terms “aryl” and “heteroaryl” refer to monocyclic andpolycyclic unsaturated or aromatic ring structures, with “aryl”referring to those that are carbocycles and “heteroaryl” referring tothose that are heterocycles. Examples of aromatic ring structuresinclude phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl,pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl,1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl(thianaphthenyl), and the like. Such moieties may be optionallysubstituted by a fused-ring structure or bridge, for example OCH₂—O.

[0077] The term “alkoxy” is intended to mean the radical -O-alkyl.Illustrative examples include methoxy, ethoxy, propoxy, and the like.

[0078] The term “aryloxy” respresents -O-aryl, wherein aryl is definedabove.

[0079] The term “cycloalkoxyl” represents -O-cycloalkyl, whereincycloalkyl is defined above.

[0080] The term “halogen” represents chlorine, fluorine, bromine oriodine. The term “halo” represents chloro, fluoro, bromo or iodo.

[0081] In general, the various moieties or functional groups forvariables in the formulae may be optionally substituted by one or moresuitable substituents. Exemplary substituents include a halogen (F, Cl,Br, or I), lower alky, —OH, —NO₂, —CN, —CO₂H, -O-lower alkyl, -aryl,-aryl-lower alkyl, —CO₂CH₃, —CONH₂, —OCH₂CONH₂, —NH₂, —SO₂NH₂, haloalkyl(e.g., —CF₃, —CH₂CF₃), -O-haloalkyl (e.g., —OCF₃, —OCHF₂), and the like.

[0082] The terms “comprising” and “including” are used in an open,non-limiting sense.

[0083] It is understood that while a compound of Formula I may exhibitthe phenomenon of tautomerism, the formula drawings within thisspecification expressly depict only one of the possible tautomericforms. It is therefore to be understood that within the invention theformulae are intended to represent any tautomeric form of the depictedcompound and is not to be limited merely to a specific tautomeric formdepicted by the formula drawings.

[0084] Some of the inventive compounds may exist as single stereoisomers(i.e., essentially free of other stereoisomers), racemates, and/ormixtures of enantiomers and/or diastereomers. All such singlestereoisomers, racemates and mixtures thereof are intended to be withinthe scope of the present invention. Preferably, the inventive compoundsthat are optically active are used in optically pure form.

[0085] As generally understood by those skilled in the art, an opticallypure compound having one chiral center is one that consists essentiallyof one of the two possible enantiomers (i.e., is enantiomerically pure),and an optically pure compound having more than one chiral center is onethat is both diastereomerically pure and enantiomerically pure.Preferably, the compounds of the present invention are used in a formthat is at least 90% optically pure, that is , a form that contains atleast 90% of a single isomer (80% enantiomeric excess (“e.e.”) ordiastereomeric excess (“d.e.”)), more preferably at least 95% (90% e.e.or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), andmost preferably at least 99% (98% e.e. or d.e.).

[0086] Additionally, the formulas are intended to cover solvated as wellas unsolvated forms of the identified structures. For example, Formula Iincludes compounds of the indicated structure in both hydrated andnon-hydrated forms. Other examples of solvates include the structures incombination with isopropanol, ethanol, methanol, DMSO, ethyl acetate,acetic acid, or ethanolamine.

[0087] In addition to compounds of the Formula I, II, III, and IV, theinvention includes pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, and pharmaceutically acceptablesalts of such compounds.

[0088] “A pharmaceutically acceptable prodrug” is a compound that may beconverted under physiological conditions or by solvolysis to thespecified compound or to a pharmaceutically acceptable salt of suchcompound.

[0089] “A pharmaceutically active metabolite” is intended to mean apharmacologically active product produced through metabolism in the bodyof a specified compound or salt thereof. Metabolites of a compound maybe identified using routine techniques known in the art and theiractivities determined using tests such as those described herein.

[0090] Prodrugs and active metabolites of a compound may be identifiedusing routine techniques known in the art. See, e.g., Bertolini, G. etal., J. Med. Chem., 40, 2011-2016 (1997); Shan, D. et al., J. Pharm.Sci., 86 (7), 765-767; Bagshawe K., Drug Dev. Res., 34, 220-230 (1995);Bodor, N., Advances in Drug Res., 13, 224-331 (1984); Bundgaard, H.,Design of Prodrugs (Elsevier Press 1985); and Larsen, I. K., Design andApplication of Prodrugs, Drug Design and Development (Krogsgaard-Larsenet al., eds., Harwood Academic Publishers, 1991).

[0091] “A pharmaceutically acceptable salt” is intended to mean a saltthat retains the biological effectiveness of the free acids and bases ofthe specified compound and that is not biologically or otherwiseundesirable. A compound of the invention may possess a sufficientlyacidic, a sufficiently basic, or both functional groups, and accordinglyreact with any of a number of inorganic or organic bases, and inorganicand organic acids, to form a pharmaceutically acceptable salt. Exemplarypharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with a mineral ororganic acid or an inorganic base, such as salts including sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, y-hydroxybutyrates, glycollates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

[0092] If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid,such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid or cinnamic acid, a sulfonic acid, such asp-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0093] If the inventive compound is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include organic salts derived from aminoacids, such as glycine and arginine, ammonia, primary, secondary, andtertiary amines, and cyclic amines, such as piperidine, morpholine andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0094] In the case of agents that are solids, it is understood by thoseskilled in the art that the inventive compounds and salts may exist indifferent crystal or polymorphic forms, all of which are intended to bewithin the scope of the present invention and specified formulas.

[0095] Therapeutically effective amounts of the agents of the inventionmay be used to treat diseases mediated by modulation or regulation ofprotein kinases. An “effective amount” is intended to mean that amountof an agent that, when administered to a mammal in need of suchtreatment, is sufficient to effect treatment for a disease mediated bythe activity of one or more protein kinases, such as tryosine kinases.Thus, e.g., a therapeutically effective amount of a compound of theFormula I, salt, active metabolite or prodrug thereof is a quantitysufficient to modulate, regulate, or inhibit the activity of one or moreprotein kinases such that a disease condition which is mediated by thatactivity is reduced or alleviated.

[0096] The amount of a given agent that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art. “Treating” is intended to mean atleast the mitigation of a disease condition in a mammal, such as ahuman, that is affected, at least in part, by the activity of one ormore protein kinases, such as tyrosine kinases, and includes: preventingthe disease condition from occurring in a mammal, particularly when themammal is found to be predisposed to having the disease condition buthas not yet been diagnosed as having it; modulating and/or inhibitingthe disease condition; and/or alleviating the disease condition.

[0097] The inventive agents may be prepared using the reaction routesand synthesis schemes as described below, employing the techniquesavailable in the art using starting materials that are readilyavailable.

[0098] In one general synthetic process, compounds of Formula I areprepared according to the following reaction scheme:

[0099] 6-Nitroindazole (compound V) is treated with iodine and base,e.g., NaOH, in an aqueous/organic mixture, preferably with dioxane. Themixture is acidified and the product isolated by filtration. To theresulting 3-iodo-6-nitroindazole in dichloromethane-50% aqueous KOH at0° C. is added a protecting group (“Pg”) reagent (wherein X=halo),preferably trimethylsilylethoxymethyl chloride (SEM-Cl), and a phasetransfer catalyst, e.g., tetrabutylammonium bromide (TBABr). After 1-4hours, the two phases are diluted, the organics are separated, driedwith sodium sulfate, filtered and concentrated. The crude product ispurified by silica gel chromatography to give compounds of formula VI.Treatment of compounds of formula VI in a suitable organic solvent witha suitable R¹-organometallic reagent, preferably an R¹-boronic acid, inthe presence of aqueous base, e.g., sodium carbonate, and a suitablecatalyst, preferably Pd(PPh₃)₄ gives, after extractive work-up andsilica gel chromatography, compounds of formula VII. The R¹ substituentmay be exchanged within compounds of formula VII or later intermediatesthroughout this scheme by oxidative cleavage (e.g., ozonolysis) followedby additions to the resulting aldehyde functionality with Wittig orcondensation transformations (typified in Example 42(a-e)). Treatment ofcompounds of formula VII with a reducing agent, preferably SnCl₂,provides, after conventional aqueous work up and purification, compoundsof formula VIII. For the series of derivatives where Y=NH or N-loweralkyl, compounds of formula VIII may be treated with aryl or heteroarylchlorides, bromides, iodides or triflates in the presence of a base,preferably Cs₂CO₃, and catalyst, preferably Pd-BINAP, (and whereY=N-lower alkyl, with a subsequent alkylation step) to provide compoundsof formula X. To produce other Y linkages, sodium nitrite is added tocompounds of formula VIII under chilled standard aqueous acidicconditions followed by the addition of potassium iodide and gentlewarming. Standard work-up and purification produces iodide compounds offormula IX.

[0100] Treatment of compounds of formula IX with an organometallicreagent, e.g., butyllithium, promotes lithium halogen exchange. Thisintermediate is then reacted with an R² electrophile, e.g., a carbonylor triflate, through the possible mediation of additional metals andcatalysts, preferably zinc chloride and Pd(PPh₃)₄ to provide compoundsof formula X. Alternatively, compounds of formula IX may be treated withan organometallic reagent such as an organoboronic acid in the presenceof a catalyst, e.g., Pd(PPh₃)₄, under a carbon monoxide atmosphere togive compounds of formula X. Alternatively, for derivatives where Y═NHor S, compounds of formula IX may be treated with appropriate amines orthiols in the presence of base, preferably Cs₂CO₃ or K₃PO₄ and acatalyst, preferably Pd-BINAP or Pd-(bis-cyclohexyl)biphenylphosphine toprovide compounds of formula X. Conventional functional groupinterchanges, such as oxidations, reductions, alkylations, acylations,condensations, and deprotections may then be employed to furtherderivatize this series giving final compounds of Formula I.

[0101] The inventive compounds of Formula I may also be preparedaccording general procedure shown in the following scheme:

[0102] 6-Iodoindazole (XI) is treated with iodine and base, e.g., NaOH,in an aqueous/organic mixture, preferably with dioxane. The mixture isacidified and the product XII is isolated by filtration. To theresulting 3,6 di-iodoindazole in dichloromethane-50% aqueous KOH at 0°C. is added a protecting group reagent, preferably SEM-Cl, and a phasetransfer catalyst, e.g., TBABr. The two phases are diluted, the organicsseparated, dried with sodium sulfate, filtered and concentrated. Thecrude product is purified by silica gel chromatography to give compoundsof the formula XIII. Treatment of compounds of formula XIII in asuitable organic solvent with a suitable R²-organometallic reagent,e.g., R²-ZnCl or boron R²-boron reagent and a suitable catalyst,preferably Pd(PPh₃)₄ gives, after extractive work-up and silica gelchromatography, compounds of formula XIV. Treatment of compounds offormula XIV in a suitable organic solvent with a suitableR¹-organometallic reagent (e.g., boron R¹-boron reagent or R¹-ZnCl), inthe presence of aqueous base, sodium carbonate, and a suitable catalyst,preferably Pd(PPh₃)₄ gives, after extractive work-up and silica gelchromatography, compounds of formula XV. Conventional functional groupinterchanges, such as oxidations, reductions, alkylations, acylations,condensations and deprotections may then be employed to furtherderivatize this series giving final compounds of Formula I.

[0103] Alternatively, compounds of Formula I where R² is a substitutedor unsubstituted Y-Ar, where Y is O or S may be prepared according tothe following general scheme:

[0104] A stirred acetone solution of 3-chloro-cyclohex-2-enone (XV),H-R², and anhydrous potassium carbonate is refluxed for 15-24 hours,cooled, and filtered. Concentrating and chromatographing the filtrate onsilica gel gives 3-R²-cyclohex-2-enone (XVI).

[0105] The ketones of formula XVI may be reacted with a suitable base(M-B), preferably lithium bis(trimethylsily)amide, and reacted withR¹—CO—X (where X=halogen), which after standard acid work up andpurification provides compounds of the formula XVII. This product, inHOAc/EtOH, combined with hydrazine monohydrate, is heated at a suitabletemperature for an appropriate time period, preferably at 60-80° C. for24 hours. After cooling, the mixture is poured into saturated sodiumbicarbonate solution, extracted with an organic solvent, concentrated,and purified on silica gel to give compounds of formula XVIII. Compoundsof formula XVIII may be oxidized using a variety of known methods togive compounds of the Formula I.

[0106] Other compounds of Formula I may be prepared in manners analogousto the general procedures described above or the detailed proceduresdescribed in the examples herein. The affinity of the compounds of theinvention for a receptor may be enhanced by providing multiple copies ofthe ligand in close proximity, preferably using a scaffolding providedby a carrier moiety. It has been shown that provision of such multiplevalence compounds with optimal spacing between the moieties dramaticallyimproves binding to a receptor. See, e.g., Lee et al., Biochem, 23, 4255(1984). The multivalency and spacing can be controlled by selection of asuitable carrier moiety or linker units. Such moieties include molecularsupports which contain a multiplicity of functional groups that can bereacted with functional groups associated with the compounds of theinvention. Of course, a variety of carriers can be used, includingproteins such as BSA or HAS, a multiplicity of peptides-including, forexample, pentapeptides, decapeptides, pentadecapeptides, and the like.The peptides or proteins can contain the desired number of amino acidresidues having free amino groups in their side chains; however, otherfunctional groups, such as sulfhydryl groups or hydroxyl groups, canalso be used to obtain stable linkages.

[0107] Compounds that potently regulate, modulate, or inhibit theprotein kinase activity associated with receptors VEGF, FGF, CDKcomplexes, TEK, CHK1, LCK, FAK, and phosphorylase kinase among others,and which inhibit angiogenesis and/or cellular profileration isdesirable and is one preferred embodiment of the present invention. Thepresent invention is further directed to methods of modulating orinhibiting protein kinase activity, for example in mammalian tissue, byadministering an inventive agent. The activity of the inventivecompounds as modulators of protein kinase activity, such as the activityof kinases, may be measured by any of the methods available to thoseskilled in the art, including in vivo and/or in vitro assays. Examplesof suitable assays for activity measurements include those described inParast C. et al., BioChemistry, 37, 16788-16801 (1998); Jeffrey et al.,Nature, 376, 313-320 (1995); WIPO International Publication No. WO97/34876; and WIPO International Publication No. WO 96/14843. Theseproperties may be assessed, for example, by using one or more of thebiological testing procedures set out in the examples below.

[0108] The active agents of the invention may be formulated intopharmaceutical compositions as described below. Pharmaceuticalcompositions of this invention comprise an effective modulating,regulating, or inhibiting amount of a compound of Formula I, II, III, orIV and an inert, pharmaceutically acceptable carrier or diluent. In oneembodiment of the pharmaceutical compositions, efficacious levels of theinventive agents are provided so as to provide therapeutic benefitsinvolving modulation of protein kinases. By “efficacious levels” ismeant levels in which the effects of protein kinases are, at a minimum,regulated. These compositions are prepared in unit-dosage formappropriate for the mode of administration, e.g., parenteral or oraladministration.

[0109] An inventive agent is administered in conventional dosage formprepared by combining a therapeutically effective amount of an agent(e.g., a compound of Formula I) as an active ingredient with appropriatepharmaceutical carriers or diluents according to conventionalprocedures. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation.

[0110] The pharmaceutical carrier employed may be either a solid orliquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin,agar, pectin, acacia, magnesium stearate, stearic acid and the like.Exemplary of liquid carriers are syrup, peanut oil, olive oil, water andthe like. Similarly, the carrier or diluent may include time-delay ortime-release material known in the art, such as glyceryl monostearate orglyceryl distearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate and the like.

[0111] A variety of pharmaceutical forms can be employed. Thus, if asolid carrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier may vary, but generally will befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation will be in the form of syrup, emulsion, soft gelatincapsule, sterile injectable solution or suspension in an ampoule or vialor non-aqueous liquid suspension.

[0112] To obtain a stable water-soluble dose form, a pharmaceuticallyacceptable salt of an inventive agent is dissolved in an aqueoussolution of an organic or inorganic acid, such as 0.3M solution ofsuccinic acid or citric acid. If a soluble salt form is not available,the agent may be dissolved in a suitable cosolvent or combinations ofcosolvents. Examples of suitable cosolvents include, but are not limitedto, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80,gylcerin and the like in concentrations ranging from 0-60% of the totalvolume. In an exemplary embodiment, a compound of Formula I is dissolvedin DMSO and diluted with water. The composition may also be in the formof a solution of a salt form of the active ingredient in an appropriateaqueous vehicle such as water or isotonic saline or dextrose solution.

[0113] It will be appreciated that the actual dosages of the agents usedin the compositions of this invention will vary according to theparticular complex being used, the particular composition formulated,the mode of administration and the particular site, host and diseasebeing treated. Optimal dosages for a given set of conditions can beascertained by those skilled in the art using conventionaldosage-determination tests in view of the experimental data for anagent. For oral administration, an exemplary daily dose generallyemployed is from about 0.001 to about 1000 mg/kg of body weight, morepreferably from about 0.001 to about 50 mg/kg body weight, with coursesof treatment repeated at appropriate intervals. Administration ofprodrugs are typically dosed at weight levels which are chemicallyequivalent to the weight levels of the fully active form.

[0114] The compositions of the invention may be manufactured in mannersgenerally known for preparing pharmaceutical compositions, e.g., usingconventional techniques such as mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orlyophilizing. Pharmaceutical compositions may be formulated in aconventional manner using one or more physiologically acceptablecarriers, which may be selected from excipients and auxiliaries thatfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically.

[0115] Proper formulation is dependent upon the route of administrationchosen. For injection, the agents of the invention may be formulatedinto aqueous solutions, preferably in physiologically compatible bufferssuch as Hanks's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art.

[0116] For oral administration, the compounds can be formulated readilyby combining the active compounds with pharmaceutically acceptablecarriers known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained using a solid excipient in admixture with theactive ingredient (agent), optionally grinding the resulting mixture,and processing the mixture of granules after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients include: fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; and cellulose preparations, for example, maizestarch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

[0117] Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

[0118] Pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillerssuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate, and, optionally, stabilizers. In softcapsules, the active agents may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration. For buccal administration, the compositions may take theform of tablets or lozenges formulated in conventional manner.

[0119] For administration intranasally or by inhalation, the compoundsfor use according to the present invention are conveniently delivered inthe form of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator and the like may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

[0120] The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit-dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

[0121] Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active agents may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

[0122] For administration to the eye, a compound of the Formula I, II,III, or IV is delivered in a pharmaceutically acceptable ophthalmicvehicle such that the compound is maintained in contact with the ocularsurface for a sufficient time period to allow the compound to penetratethe corneal and internal regions of the eye, including, for example, theanterior chamber, posterior chamber, vitreous body, aqueous humor,vitreous humor, cornea, iris/cilary, lens, choroid/retina and selera.The pharmaceutically acceptable ophthalmic vehicle may be an ointment,vegetable oil, or an encapsulating material. A compound of the inventionmay also be injected directly into the vitreous and aqueous humor.

[0123] Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use. The compounds may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g, containing conventionalsuppository bases such as cocoa butter or other glycerides.

[0124] In addition to the formulations described above, the compoundsmay also be formulated as a depot preparation. Such long-actingformulations may be administered by implantation (for example,subcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example, as an emulsion in an acceptable oil)or ion-exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

[0125] A pharmaceutical carrier for hydrophobic compounds is a cosolventsystem comprising benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. The cosolventsystem may be a VPD co-solvent system. VPD is a solution of 3% w/vbenzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.The VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5%dextrose in water solution. This co-solvent system dissolves hydrophobiccompounds well, and itself produces low toxicity upon systemicadministration. Naturally, the proportions of a co-solvent system may bevaried considerably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the co-solvent componentsmay be varied: for example, other low-toxicity nonpolar surfactants maybe used instead of polysorbate 80; the fraction size of polyethyleneglycol may be varied; other biocompatible polymers may replacepolyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars orpolysaccharides may be substituted for dextrose.

[0126] Alternatively, other delivery systems for hydrophobicpharmaceutical compounds may be employed. Liposomes and emulsions areknown examples of delivery vehicles or carriers for hydrophobic drugs.Certain organic solvents such as dimethylsulfoxide also may be employed,although usually at the cost of greater toxicity. Additionally, thecompounds may be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are known by those skilled in the art. Sustained-releasecapsules may, depending on their chemical nature, release the compoundsfor a few weeks up to over 100 days. Depending on the chemical natureand the biological stability of the therapeutic reagent, additionalstrategies for protein stabilization may be employed.

[0127] The pharmaceutical compositions also may comprise suitable solid-or gel-phase carriers or excipients. Examples of such carriers orexcipients include calcium carbonate, calcium phosphate, sugars,starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

[0128] Some of the compounds of the invention may be provided as saltswith pharmaceutically compatible counter ions. Pharmaceuticallycompatible salts may be formed with many acids, including hydrochloric,sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend tobe more soluble in aqueous or other protonic solvents than are thecorresponding free-base forms.

[0129] The preparation of preferred compounds of the present inventionis described in detail in the following examples, but the artisan willrecognize that the chemical reactions described may be readily adaptedto prepare a number of other protein kinase inhibitors of the invention.For example, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by changing to other suitable reagents known in the art, or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

EXAMPLES

[0130] In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius and all parts andpercentages are by weight. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd.and were used without further purification unless otherwise indicated.Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane,toluene, and dioxane were purchased from Aldrich in Sure seal bottlesand used as received. All solvents were purified using standard methodsreadily known to those skilled in the art, unless otherwise indicated.

[0131] The reactions set forth below were done generally under apositive pressure of argon or nitrogen or with a drying tube, at ambienttemperature (unless otherwise stated), in anhydrous solvents, and thereaction flasks were fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. Analytical thin layer chromatography (TLC) was performed onglass-backed silica gel 60 F 254 plates Analtech (0.25 mm) and elutedwith the appropriate solvent ratios (v/v), and are denoted whereappropriate. The reactions were assayed by TLC and terminated as judgedby the consumption of starting material.

[0132] Visualization of the TLC plates was done with a p-anisaldehydespray reagent or phosphomolybdic acid reagent (Aldrich Chemical 20 wt %in ethanol) and activated with heat. Work-ups were typically done bydoubling the reaction volume with the reaction solvent or extractionsolvent and then washing with the indicated aqueous solutions using 25%by volume of the extraction volume unless otherwise indicated. Productsolutions were dried over anhydrous Na₂SO₄ prior to filtration andevaporation of the solvents under reduced pressure on a rotaryevaporator and noted as solvents removed in vacuo. Flash columnchromatography (Still et al., J. Org. Chem., 43, 2923 (1978)) was doneusing Baker grade flash silica gel (47-61 μm) and a silica gel: crudematerial ratio of about 20:1 to 50:1 unless otherwise stated.Hydrogenolysis was done at the pressure indicated in the examples or atambient pressure.

[0133]¹H-NMR spectra were recorded on a Bruker instrument operating at300 MHz and ¹³C-NMR spectra were recorded operating at 75 MHz. NMRspectra were obtained as CDCl₃ solutions (reported in ppm), usingchloroform as the reference standard (7.25 ppm and 77.00 ppm) or CD₃OD(3.4 and 4.8 ppm and 49.3 ppm), or internally tetrarnethylsilane (0.00ppm) when appropriate. Other NMR solvents were used as needed. When peakmultiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd(doublet of doublets), dt (doublet of triplets). Coupling constants,when given, are reported in Hertz (Hz).

[0134] Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IRSpectrometer as neat oils, as KBr pellets, or as CDCl₃ solutions, andwhen given are reported in wave numbers (cm⁻¹). The mass spectra wereobtained using LSIMS or electrospray. All melting points (mp) areuncorrected.

Example 1(a):3-[E-2-(3,4-Dimethoxy-phenyl)vinyl]-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

[0135]

[0136] The3-[E/Z-2-(3,4-dimethoxy-phenyl)vinyl]-6-[3-methoxy-4-(methoxymethoxy)phenyl]-1H-indazole(˜205 mg, 0.461 mmol (theoretical)) was dissolved in tetrahydrofuran(THF, 10 mL) and was treated with water (10 mL) and trifluoroacetic acid(TFA, 20 mL). The reaction mixture was allowed to stir at 23° C/ for 30minutes (min.). The mixture was diluted with toluene (100 mL) and thevolatile materials were removed under reduced pressure (30 mm Hg, 35°C.) to give a concentrated volume of ˜5 mL. Again, toluene (100 mL) wasadded and the mixture was concentrated under reduced pressure to givecrude material which still contained some acid. The material waspartitioned between ethyl acetate and saturated sodium bicarbonate, theorganic material was separated, dried over sodium sulfate, decanted, andconcentrated under reduced pressure. The residue, a mixture of olefinisomers, (˜185 mg, 0.461 mmol (theoretical)) was taken up indichloromethane (50 mL) at 23° C. and was treated with iodine (80 mg).The mixture was allowed to stir at 23° C. for 12 hours (h). The mixturewas treated with saturated sodium bicarbonate (10 mL) and 5% aqueoussodium bisulfite (10 mL). The mixture was diluted with ethyl acetate(200 mL) and the organic material was washed with saturated sodiumbicarbonate (100 mL), dried over sodium sulfate, decanted, andconcentrated under reduced pressure to give crude product. The crude waspurified on silica (40 mL, 6:4->7:3 ethyl acetate/hexane) and allfractions containing desired were combined, concentrated andprecipitated from a dichloromethane/hexane bilayer (1:3) to give3-[E-2-(3,4-Dimethoxy-phenyl)vinyl]-6-(3-methoxy4-hydroxy-phenyl)-1H-indazoleas a white solid (93 mg combined crops): R_(f) sm 0.42, p 0.35 (ethylacetate-hexane 7:3); FTIR (thin film) 3324, 1600, 1514, 1463, 1422,1264, 1137, 1024,959,852 cm⁻¹; ¹H NMR (CDC1₃) δ 10.0 (bs, 1H), 8.08 (d,1H, J=8.4 Hz), 7.59 (s, 1H), 7.49 (d, 1H, J=16.6 Hz), 7.45 (dd, 1H,J=1.4, 8.4 Hz), 7.34 (d, 1H, J=16.6 Hz), 7.20-7.12 ( m, 4H), 7.03 (d,1H, J=8.0 Hz), 6.91 (d, 1H, J=8.2 Hz), 5.68 (bs, 1H), 3.99 (s, 3H), 3.97(s, 3H), 3.93 (s, 3H); ¹³C NMR (CDCl₃) δ 149.6, 149.5, 146.0, 144.0,142.6, 140.8, 133.9, 131.4, 130.7, 121.7, 121.4, 120.9, 120.4, 120.2,118.6, 115.4, 111.7, 110.8, 109.1, 108.2, 56.4, 56.3, 56.2. HRMS (ES)[m+H]/z Calc'd 403.1658, found 403.1658. [m-H]/z Calc'd 401. Found 401.

[0137] The starting material was prepared as follows:

[0138] To 6-aminoindazole (40.8 g, 0.3065 mol, 1 equiv) in a 2-liter(2-L) round-bottom flask containing a large magnetic stir bar was addedice (256 g), followed by water (128 mL) and the reaction vessel waslowered into an ice bath. To this stirring slurry at 0° C. was addedconcentrated aqueous HCI (128 mL, 1.53 mol, 5 equiv). Immediately after,a solution of NaNO₂ (23.3 g, 0.338 mol, 1.1 equiv) in water (96 niL) wasadded. After 10 min of stirring at 0° C., KI (61 g, 0.368 mol, 1.2equiv) was added very slowly at first (˜100 mg at a time because thefirst small bits of KI cause an abrupt evolution of gas) then morerapidly (5 min total time). The cold bath was removed and the reactionmixture was warmed to 40° C. (gas evolved). When the rate of gasevolution decreased (˜30 min) the reaction mixture was warmed to 50° C.for 30 min. The mix was then cooled to 23° C., and 3N NaOH (320 mL) wasadded to neutralize followed by 50% saturated NaHCO₃ (320 mL). Theslurry was then filtered through a Buchner funnel to give a darkreddish-brown solid. The solid was taken up in warm THF (800 mL) andsilica (600 mL dry) was added with stirring. To this slurry was addedhexane (1.2 L) and the mix was vacuum filtered through a pad of silica(300 mL) in a large fritted filter. The silica was further washed with 2L of 40% THF in hexane. The filtrates were combined and concentratedunder reduced pressure to give a solid. The solid was further trituratedwith ethyl acetate (˜100 mL), filtered and dried under reduced pressureto give 6-iodo-1H-indazole as a light brown solid (36.1 g, 48% yield):R_(f) sm 0.12, p 0.48 (Hex-EtOAc 1:1); ¹H NMR (300 MHz, CDCl₃) 7.9 (s,1H), 7.8 (s, 1H), 7.42 (d, 1H), 7.33 (d, 1H); MS (ES) [m+H]/z Calc'd245, Found 245, [m-H]/z Calc'd 243, Found 243.

[0139] To a solution of 6-iodo-1H-indazole (7.35 g, 30.1 mmol, 1 equiv)in THF (100 mL) cooled to 0° C. under argon, was added sodium t-butoxide(2.89 g, 30.1 mmol, 1 equiv). A color change from orange to red wasobserved. Mesitylenesulfonyl chloride (6.60 g, 30.1 mmol, 1 equiv) wasadded in one portion and the ice bath was removed allowing the reactionmixture to warm to 23° C. After 40 min the mixture was quenched withsaturated ammonium chloride and partitioned between water and ethylacetate. The aqueous was extracted a total of 3 times with ethylacetate. The combined organic material was washed with brine, dried oversodium sulfate and concentrated under reduced pressure to give6-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole as an orangesolid (12.8 g, 100% yield, 2:1 mixture). ¹H NMR (CDCl₃) 8.51 (s, 1H),7.95 (s, 0.66H, major isomer), 7.91 (s, 0.33H, minor isomer), 7.47 (d,0.33H, J=8.4 Hz), 7.29 (d, 0.33H, J=8.4 Hz), 7.26 (d, 0.66H, J=8.9 Hz),7.18 (d, 0.66H, 8.9 Hz), 6.84 (s, 2H), 2.51 (s, 6H), 2.15 (s, 3H).

[0140] (iii)

[0141] A mixture of6-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole (5.78 g, 13.56mmol, 1.00 equiv) and 3-methoxy4-(methoxymethoxy)benzene-boronic acid(3.45 g, 16.27 mmol, 1.20 equiv) under argon was dissolved in dioxane(15 mL) and water (2.0 mL). To this solution was added triethylamine(2.83 mL, 20.3 mmol, 1.5 equiv), potassium carbonate (2.8 g, 20.3 mmol,1.5 equiv) and dichlorobis(triphenylphosphine)palladium (476 mg, 0.678mmol, 0.05 equiv). The reaction mixture was heated to 90° C. for 2 h andthen was cooled to 23° C. The mixture was separated between ethylacetate (250 mL) and saturated sodium bicarbonate (150 mL). The organicmaterial was dried over sodium sulfate, decanted and concentrated underreduced pressure to give crude6-(3-methoxy4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazolethat was dried under high vacuum for 15 h and was used without furtherpurification.

[0142] 3-Methoxy-4-(methoxymethoxy)benzeneboronic acid was prepared asfollows: In a 100 mL flask a mixture of 50% KOH in water (20 g KOH, 7equiv, 20 g ice) was prepared under argon. To this rapidly stirringmixture at 0° C. (maintained with an ice bath) was added dichloromethane(50 mL) followed by 4-bromo-2-methoxyphenol (10.1 g, 50 mmol, 1.00equiv), methoxymethylchloride (MOMCl) (4.00 mL, 42.5 mmol, 1.05 equiv)and tetrabutylammonium bromide (322 mg, 1 mmol, 0.02 equiv). The bathwas removed and the mixture was slowly allowed to warm to 23° C. withrapid stirring for 2 h. The mixture is transferred to a separatoryfunnel and diluted with dichloromethane (350 mL) and water (300 mL)which are used to aid the transfer. The organic material (now the bottomlayer) are separated, dried over sodium sulfate, decanted andconcentrated under reduced pressure to give4-bromo-2-methoxy-1-(methoxymethoxy)benzene as a yellow liquid which ispure by ¹H NMR (11.9 g, 97%): ¹H NMR (CDCl₃) δ 7.0 (s, 3H), 5.13 (s,2H), 3.84 (s, 3H), 3.47 (s, 3H). MS (E1) [m+H]/z Calc'd 235, found 235.In a 50 mL round-bottom flask,4-bromo-2-methoxy-1-(methoxymethoxy)benzene (4.80 g, 19.4 mmol, 1.00equiv) was taken up in THF (35 mL) and was cooled to −78° C. (20 min forthis volume). To this was added n-BuLi (12.75 mL, 1.6 M in hexane, 20.4mmol, 1.05 equiv) and the mixture was allowed to stir at −78° C. for 40min. This was then added via cannula to a second flask containingB(OMe)₃ (22 mL, 194 mmol, 10 equiv) in THF (50 mL) at −78° C. After 20min, the cold bath was removed. After 15 min of warming (˜0° C., ice onthe side of the flask begins to melt) water (50 mL) was added to thereaction mixture which was stirred for 45 min. The mixture wasconcentrated under reduced pressure to remove most THF and was thenpartitioned between ethyl acetate (300 mL) and water (150 mL) which wasmade acidic by addition of a small amount of 20% citric acid (˜10 mL).The organic material was dried over sodium sulfate and concentratedunder reduced pressure to give a solid. Trituration with ethyl acetate(10 mL) and hexane (5 mL) followed by filtering gave3-methoxy-4-(methoxymethoxy)benzene-boronic acid as a white solid (3.15g, 77%): R_(f) sm 0.59, p 0.18 (ethyl acetate-hexane 1:1); ¹H NMR(CDCl₃) δ 7.85 (d, 1H, J=8 Hz), 7.72 (s, 1H), 7.22 (d, 1H, J=8 Hz), 5.30(s, 2H), 4.00 (s, 3H), 3.55 (s, 3H).

[0143] Unpurified6-(3-methoxy4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole(under argon) was dissolved in THF (20 mL) and was treated with IN NaOHin MeOH (70 mL degassed by bubbling through argon for 3 to 5 min). Themixture was heated to 45° C. for 1 h and allowed to cool. The mixturewas neutralized by addition of IN HCI (50 mL) followed by saturatedsodium bicarbonate (200 mL). The product was extracted into ethylacetate (350 mL), dried over sodium sulfate and concentrated underreduced pressure to give crude6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole. Purification bysilica gel chromatography (500 mL silica, 20% ethyl acetate in benzene(1.8 L), 30% ethyl acetate in benzene (1.8 L)) gave6-(3-methoxy4-methoxymethoxy-phenyl)-1H-indazole (1.19 g, 31%): ¹H NMR(CDCl₃) 8 7.80 (s, 1H), 7.69 (d, 1H, J=8.5 Hz), 7.52 (s, 1H), 7.29 (d,1H, J=8.5 Hz), 7.16 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H). MS (ES)[m+Na]/z Calc'd 337, found 337; [m+Cl-]/z Calc'd 349, found 349.

[0144] In a 100-miL round-bottom flask under argon,6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (1.19 g, 4.18 mmol, 1equiv) was dissolved in dioxane (25 mL) and 3N NaOH (14 mL). Thismixture was treated with iodine (1.17 g, 14.60 mmol, 1.10 equiv) addedin ˜5 portions (˜10 min). Several (˜4) additional portions of iodine (50mg each) were added until the reaction was complete as acetate/hexane)gave 6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde(498 mg, 71%)): R_(f) sm 0.30, p 0.14 (ethyl acetate-hexane 4:6); ¹H NMR(CDCl₃) δ 10.85 (bs, 1H), 10.25 (s, 1H), 8.37 (d, 1H, J=8.4 Hz), 7.67(s, 1H), 7.60 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=8.7 Hz), 7.19 (m, 2H),5.30 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).

[0145] 6-(3-methoxy4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde(441 mg, 1.41 mmol, 1.0 equiv) was taken up as a suspension indichloromethane (15 mL) and was cooled to 0° C. This mixture was treatedwith mesitylene sulfonyl chloride (324 mg, 1.48 mmol, 1.05 equiv) anddimethylamino pyridine (DMAP) (181 mg, 1.48 mmol, 1.05 equiv). Themixture was allowed to stir for 1 h at 0° C. and was quenched with theaddition of water. The mixture was partitioned between water and a 1:1ethyl acetate/hexane organic layer. The organic material was dried oversodium sulfate, decanted and concentrated under reduced pressure to givecrude material which was purified by silica gel chromatography (50 mLsilica, 3:7 ethyl acetate/hexane) to give6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole-3-carbaldehyde(374 mg, 54%): R_(f) sm 0.17, p 0.53 (ethyl acetate-hexane 4:6); ¹H NMR(CDCl₃) δ 10.20 (s, 1H), 8.41 (s, 1H), 8.37 (d, 1H, J=8.5 Hz), 7.73 (dd,1H, J=1.4, 8.4 Hz), 7.3 (m, 3H), 7.08 (s, 2H), 5.36 (s, 2H), 4.08 (s,3H), 3.71 (s, 3H), 2.74 (s, 6H), 2.40 (s, 3H).

[0146] Finely ground triphenyl(3,4-dimthoxybenzyl)phosphonium bromide(1.09 g, 2.22 mmol, 4.0 equiv) was taken up as a slurry in THF (15 mL)and was cooled to −78° C. To this mixture was added n-BuLi (1.04 mL, 1.6M, 1.66 mmol, 3.0 equiv) which gave a red/orange solution. The mixturewas allowed to warm to 23° C. for 1 h. This mixture was then added to a0° C. solution of6-(3-methoxy4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole-3-carbaldehyde(274 mg, 0.554 mmol, 1.0 equiv) in THF (5 mL) via cannula. The resultingmixture was allowed to stir at 0° C. for 10 min and was quenched withsaturated sodium bicarbonate. The resulting mixture was partitionedbetween saturated sodium bicarbonate and ethyl acetate. The organicmaterial was concentrated under reduced pressure and the residue waspurified by silica gel chromatography (50 mL silica, 3:7->4:6 ethylacetate/hexane) to give a 2.5:1 mixture of cis/trans3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole(289 mg, 83%): R_(f) sm 0.53, p 0.32 (ethyl acetate-hexane 4:6); ¹H NMR(CDCl₃) δ 8.35 (s, 0.3H), 8.32 (s, 0.7H), 8.03 (d, 0.3H, J=8.4 Hz),7.60-6.85 (m, H), 6.65 (d, 0.7H, J=8.4 Hz), 6.60 (d, 0.7H, J=12.5 Hz),5.30 (s, 0.6H), 5.29 (s, 1.4H), 4.00-3.50 (8 singlets, 12H), 2.72 (s,1.8H), 2.67 (s, 4.2H), 2.34 (s, 3H); MS (ES) [m+H]/z Calc'd 629, found629, [m-H]/z Calc'd 627, found 627.

[0147] A 1M solution of KOH (1.0 g, 17.8 mmol) in 1:1 water/MeOH (18 mLtotal) was prepared under argon and was degassed by vacuum/purge cycleswith argon (5 times). In a separate flask,3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole(289 mg, 0.461 mmol, 1.0 equiv) was dissolved in THF (8 mL) under argon.To this solution was added the above IM KOH solution (10 mL, 1:1water/MeOH). The reaction was warmed to 30° C. and was allowed to stirfor 7 h. The reaction mix was neutralized by the addition of 20% citricacid (7 mL). The resulting mix was partitioned between ethyl acetate(150 mL) and water (100 mL). The organic material was separated, driedover sodium sulfate, decanted, and concentrated under reduced pressureto give cis and trans3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy4-methoxymethoxy-phenyl)-1H-indazole(used crude): R_(f) sm 0.46, pl 0.17, p2 0.23 (ethyl acetate-hexane1:1); ¹H NMR cis isomer (CDCl₃) δ 7.55 (s, 1H), 7.3-7.1 (m, 6H), 7.02(dd, 1H, J=1.9, 8.3 Hz), 6.85 (d, 1H, J=12.5 Hz), 6.78 (d, 1H, J=12.5Hz), 6.74 (d, 1H, J=8.3 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.70 (s, 3H),3.43 (s, 3H), 3.42 (s, 3H). MS (ES) [m+H]/z Calc'd 447, found 447,[m-H]/z Calc'd 445, found 445.

Example 1(b): 3-(E-styryl)-6-(3-benzyloxy-4-hydroxy-phenyl)-1H-indazole

[0148]

[0149] Example 1(b) was prepared in a similar manner to that describedfor Example 1 (a), except that 4-bromo-2-benzyloxy-phenol was used instep(iii) in place of 4-bromo-2-methoxy-phenol. R_(f) sm 0.35, p 0.30(ethyl acetate-hexane 4:6); ¹H NMR (CDCl₃) δ 8.06 (d, 1H, J=8.6 Hz),7.63-7.18 (m, 17H), 7.05 (d, 1H, J=8.2 Hz), 5.19 (s, 2H). MS (CI)[m+H]/z Calc'd 419, found 419, [m-H]/z Calc'd 417, found 417.

Example 1(c):3-[E-2-(3,4-Dimethoxy-phenyl)vinyl]-6-(3-allyloxy-4-hydroxy-phenyl)-1H-indazole

[0150]

[0151] Example 1(c) was prepared in a similar manner to that describedfor Example 1(a), except that3-allyloxy4-(methoxymethoxy)benzene-boronic acid was used instead of3-methoxy4-(methoxymethoxy)benzene-boronic acid in step (iii). MS (ESI)[M+H]/z Calc'd 429, found 429; MS (ESI) [M-H]/z Calc'd 427, found 427.

Example 2(a):3-(Naphthalen-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

[0152]

[0153] 6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole(25 mg, 0.055 mmol) was dissolved in a mixture of ethyl acetate (2 mL),benzene (2 mL) and methanol (2 mL). To this solution was added palladiumon carbon (25 mg, 10% wt) and the reaction vessel was vacuum/purged withhydrogen gas for five cycles. The reaction mixture was allowed to stirfor 3 days (d) at 23° C. and was filtered through a plug of Celite.Concentration and purification by silica gel chromatography afforded3-(Naphthalen-2-yl)-6-(3-methoxy4-hydroxy-phenyl)-1H-indazole (8 mg,40%): 1H NMR (CDCl₃) δ 10.3 (bs, 1H), 8.50 (s, 1H), 8.20 (d, 1H, J=8Hz), 7.98 (d, 1H, J=8 Hz), 7.90 (m, 1H), 7.7-6.8 (m, 9H), 3.98 (s, 3H).MS (ES) [m+H]/z Calc'd 367, found 367, [m-H]/z Calc'd 365, found 365.

[0154] The starting material was prepared as follows:

[0155] 2-Bromonaphthalene (117 mg, 0.564 mmol, 6.0 equiv) was dissolvedin THF (0.75 mL) and cooled to −78° C. The mixture was treated withn-BuLi (226 μL, 2.5 M, 6.0 equiv) and was allowed to stir at −78° C. for30 min. The mixture was then added to freshly dried ZnCI₂ solid (139 mg,0.80 mmol, 8.5 equiv) via cannula and the resulting mix was allowed towarm to 23° C. (during the addition the yellow color disappears). After30 min at-23° C. the mixture is added to a mixture of6-(4-benzyloxy-3-methoxy-phenyl)-3-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole(60 mg, 0.094 mmol, 1 equiv) and Pd(PPh₃)₄ (6 mg, 0.005 mmol, 0.05equiv) via cannula. The resulting solution was allowed to stir for 16 h.Saturated sodium bicarbonate was added and the mixture was partitionedbetween saturated sodium bicarbonate (15 mL) and ethyl acetate (15 mL).The organic material was dried over sodium sulfate, decanted andconcentrated. Purification by silica gel chromatography (1:9 -2:8 ethylacetate-hexane) gave6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazoleas a solid (42 mg, 70%): R_(f) sm 0.4, p 0.4 (ethyl acetate-hexane 3:7);¹H NMR (CDCl₃) δ 8.44 (s, 1H), 8.41 (s, 1H), 8.12 (d, 1H, J=8 Hz),8.05-7.00 (m, 17H), 5.30 (s, 2H), 4.02 (s, 3H), 2.80 (s, 3H), 2.34 (s,3H).

[0156]6-(4-benzyloxy-3-methoxy-phenyl)-3-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazolewas prepared in a similar manner as described in Example 1(a), steps (i)to (v).

[0157]6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazolewas converted to6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole asdescribed in Example 1(a), step (ix). R_(f) sm 0.40, p 0.17 (ethylacetate-hexane 3:7); 1H NMR (CDCl₃) δ 8.40 (s, 1H), 8.12 (d, 1H, J=8.5Hz), 8.10 (dd, 1H, J=1.6, 8.4 Hz), 7.93 (d, 1H, J=8.3 Hz), 7.88 (m, 2H),7.61 (m, 1H) 7.56 (s, 1H), 7.43 (m, 5H), 7.30 (m 3H), 7.15 (d, 1H, J=2.0Hz), 7.08 (dd, 1H, J=2.1, 8.3 Hz), 6.91 (d, 1H, J=8.3 Hz), 5.16 (s, 2H),3.91 (s, 3H).

Example 2(b): 3-phenyl-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

[0158]

[0159] Example 2(b) was prepared in a similar manner to that describedfor Example 2(a), except that phenyllithium was used in place of2-napthyllitium generated from 2-bromonaphthylene in step (i). ¹H NMR(300 MHz, CDCl₃) 8 7.87 (d, 1H), 7.83 (d, 2H), 7.55-7.27 (m, SH), 7.01(m, 2H), 6.80 (d, 1H), 3.83 (s, 3H). MS (ES) [m+H]/z Calc'd 317, Found317, [m-H]/z Calc'd 315, found 315.

Example 2(c):3-(3,4,5-trimethoxyphenyl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

[0160]

[0161] Example 2(c) was prepared in a similar manner to that describedfor Example 2(a), except that 3,4,5-trimethoxyphenyl bromide was used instep (i) in place of 2-bromonaphthylene. R_(f) sm 0.67, p 0.38 (ethylacetate-hexane 8:2); ¹H NMR (CDCl₃) δ 7.93 (d, 1H, J=8 Hz), 7.58 (s,1H), 7.39 (d, 1H, J=8 Hz), 7.10 (m, 4H), 6.92 (d, 1H, J=8 Hz), 3.90 (s,9H), 3.85 (s, 3H); MS (ES) [m+H]/z Calc'd 407, Found 407, [m-H]/z Calc'd405, Found 405.

Example 2(d): 3-(1H-Indol-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

[0162]

[0163] Example 2(d) was prepared in a similar manner to that describedfor Example 2(a) above, except that 1-phenylsulfonyl-indazole was usedin place of 2-bromonaphthylene in step (i). R_(f) sm 0.20, p 0.15 (ethylacetate-hexane 4:6); ¹H NMR (CDCl₃) δ 10.0 (bs, 1H), 9.05 (bs, 1H), 8.01(d, 1H, J=8.0 Hz), 7.55 (d, 1H, J=8.0 Hz), 7.49 (s, 1H), 7.37 (d, 1H,J=8 Hz), 7.29 (d, 1H, J=8 Hz), 7.2-7.1 (m, 5H), 6.92 (d, 1H, J=8 Hz),5.63 (bs, 1H); MS (ES) [m+H]/z Calc'd 356, Found 356; [m-H]/z Calc'd354, found 354.

Example 2(e):3-(Benzofuran-2-yl)-6-(3-benzyloxy-4-hydroxy-phenyl)-1H-indazole

[0164]

[0165] Example 2(e) was prepared in a similar manner to that describedfor Example 2(a) above, except that benzofuran was used in place of2-bromonaphthylene in step (i). ¹H NMR (CDCl₃) 6 8.21 (d, 1H, J=8.0 Hz),7.60 (m, 3H), 7.30-7.10 (m, 12H), 7,01 (d, 1H, J=8 Hz), 5.82 (bs, 1H),5.15 (s, 3H). Example 3: 3-(1H-Indol-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

[0166]3-(1H-Benzoimidazol-2-yl)-6-(3-methoxy4-methoxymethoxy-phenyl)-1H-indazolewas converted to4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-2-methoxy-phenol accordingto the procedure described in Example 1 (a) (3.5 mg, 28%). HRMS (FAB)[m+H]/z Calc'd 357.1351, Found 357.1349.

[0167] The starting material was prepared as follows:

[0168] 6-(3-Methoxy4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde(from Example 1 (a), step (vi)) (20 mg, 0.064 mmol, 1 equiv) wasdissolved in degassed 1:1 MeOH-water (0.7 mL) and was treated withacetic acid (19 μL, 5 equiv), 1,2-diaminobenzene (8.3 mg, 1.2 equiv) andcopper(II) acetate (18 mg, 1.4 equiv) at 23° C. The mixture stirred for30 min, was diluted with ethanol (3 mL) and water (2 mL) and was treatedwith a bubbling stream of SH₂ for 3 min, which gave a black precipitate.The mixture was allowed to stir for 12 h. The mixture was filtered andconcentrated. Purification by silica gel chromatography (6:4 ethylacetate-hexane) gave3-(1H-benzoimidazol-2-yl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazoleas a solid (14 mg, 54%); R_(f) sm 0.39, p 0.24 (ethyl acetate-hexane6:4); ¹H NMR (CDCl₃) δ 8.69 (d, 1H, J=8 Hz), 7.70 (bs, 2H), 7.58 (s,1H), 7.53 (d, 1H, J=8 Hz), 7.30-7.15 (m, 7H), 5.30 (s, 2H), 3.97 (s,3H), 3.58 (s, 3H); MS (ES) [m+H]/z Calc'd 401, found 401, [m-H]/z Calc'd399, found 399.

Example 4(a): N-[3-(3-Styryl-1H-indazol-6-yloxy)-phenyl]-benzamide

[0169]

[0170] A solution ofN-[3-(2-benzoyl-3-styrl-1H-indazol-6-yloxy)-phenyl]-benzamide (0.09 g,0.17 mmol) in 2 mL of 6N HCI (aqueous) and 3 mL of MeOH was heated at65° C. for about 4 h. The cooled solution was poured cautiously intosaturated sodium bicarbonate solution. The precipitate was filtered,collected and chromatographed on silica gel eluting hexanes/EtOAc (1:1).N-[3-(3-Styryl-1H-indazol-6-yloxy)-phenyl]-benzamide was obtained as abeige solid (32 mg, 50%): ¹H NMR (DMSO-d6) δ 13.50 (s, 1H), 10.32 (s,1H), 8.23 (d, 1H, J=8.7 Hz), 7.92 (d, 2H, J=6.8 Hz), 7.72 (d, 2H, J=7.3Hz), 7.71-7.51 (m, 7H), 7.51 -7.47 (m, 3H), 7.30 (t, 1H, J=7.2 Hz), 7.05(s, 1H), 7.01 (d, 1H, J=8.7 Hz), 6.86 (dd, 1H, J=8.2, 2.3 Hz). Anal.Calc. for C₂₈H₂₁N₃O₂.0.3H₂O: C, 76.97; H, 4.98: N, 9.62. Found: C,76.94; H, 5.13; N, 9.40.

[0171] The starting material was prepared as follows:

[0172] A suspension of the 3-(benzhydrylidene-amino)-phenol (10.47 g,38.3 mmol), 3-chloro-cyclohex-2-enone (5.00 g, 38.3 mmol) and potassiumcarbonate (5.82, 42.1 mmol) in 150 mL of acetone was heated at refluxovernight. The cooled reaction mixture was filtered and concentratedunder reduced pressure. The residue was chromatographed on silica geleluting hexanes/EtOAc (2:1). In this manner,3-[3-(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone was obtained as ayellow solid, (8.82 g, 63%): ¹H NMR (CDCl₃) δ 7.78 (d, 2H, J=7.0 Hz),7.50 (d, 1H, J=7.1 Hz), 7.45 (d, 2H, J=7.7 Hz), 7.34-7.10 (m, 6H), 6.69(d, 1H, J=8.0 Hz), 6.61 (d, 1H, J=8.0 Hz), 6.38 (s, 1H), 4.89 (s, 1H),2.55 (t, 2H, J=6.2 Hz), 2.34 (t, 2H, J=6.2 Hz), 2.06 (m, 2H). Anal.Calc. for C₂₅H₂₁NO₂ 0.2H₂0: C, 80.92; H, 5.81; N, 3.78. Found: C, 81.12;H, 5.81; N, 3.72.

[0173] 3-(Benzhydrylidene-amino)-phenol was prepared as follows: Astirred solution of benzophenone imine (15.0 g, 82.8 mmol) and3-aminophenol (9.03 g, 82.8 mmol) in 25 mL toluene was heated at refluxwith removal of H₂0 with a Dean-Stark trap for 3.5 h. The crystals thatformed from the cooled reaction mixture were collected by vacuumfiltration, washed with hexanes and air dried. In this manner,3-(benzhydrylidene-amino)-phenol was obtained as a light yellow solid(17.3 g, 76%): ¹H NMR (CDCl₃) δ 7.64 (d, 2H, J=7.1 Hz), 7.38 (d, 1H,J=7.1 Hz), 7.34 -7.15 (m, 7H), 7.04 (d, 2H, J=7.2 Hz), 6.88 (t, 1H,J=8.1 Hz), 6.82 (d, 1H, J=8.2 Hz), 6.23 (s, 1H), 6.21 (d, 1H, J=7.8 Hz).Anal. Calc. for Cl₉Hl₅NO: C, 83.49; H, 5.53; N, 5.12. Found: C, 83.51;H, 5.65; N, 5.03.

[0174] A solution of3-[3-(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone (4.37 g, 11.89mmol) in 20 mL of THF was added slowly to a solution of LiHMDS (25.0 mLof 1.0 M solution in THF) in 10 mL of THF at −78° C. Five minutes afterthe addition was complete trans-cinnamoyl chloride (1.98 g, 11.89 mmol)was added all at once, and stirring was continued at −78° C. for 30 min.The reaction was quenched with saturated NH₄CI solution. And extractedwith EtOAc (2×). The combined organic layers were washed with saturatedNaCl solution, dried (MgSO₄) and concentrated under reduced pressure.The residue was chromatographed on silica gel eluting hexanes/EtOAc (5:1). In this manner,3-[3-(benzhydrylidene-amino)-phenol]-6-(3-phenyl-acryloyl)-cyclohex-2-enonewas obtained as a yellow-orange solid (3.34 g, 56%): ¹H NMR(CDCl₃)δ:15.69 (s, 1H), 7.80 (d, 2H, J=7.1 Hz), 7.63-7.01 (m, 15H), 6.93 (d,1H, J=15.6 Hz), 6.75 (d, 1H, J=7.6 Hz), 6.66 (d, 1H, J=8.0 Hz), 6.46 (s,1H), 4.92 (s, 1H), 2.85 (t, 2H, J=7.2 Hz), 2.62 (t, 2H, J=7.2 Hz). Anal.Calc. for C₃₄H₂₇NO₃: C, 82.07; H, 5.47; N, 2.82. Found: C, 81.88; H,5.53; N, 2.81.

[0175] To a stirred solution of3-[3-(benzhydrylidene-amino)-phenol](3-phenyl-acryloyl)-cyclohex-2-enone(1.81 g, 3.64 mmol) dissolved in 10 mL of HOAc/EtOH(1:1) was addedhydrazine hydrate (2.0 mL, 41.23 mmol). The solution was heated at 75°C. for 25 min. After cooling, the reaction mixture was cautiously pouredinto saturated sodium bicarbonate solution and extracted with EtOAc(2×). The combined organic layer was washed with saturated NaClsolution, dried (MgSO₄) and concentrated under reduced pressure. Theresidue was chromatographed on silica gel eluting hexanes/EtOAc (1:1).3-(3-Styryl-4, 5-dihydro-1H-indazol-6-yloxy)-phenylamine was obtained asa yellow solid (539 mg, 45%). ¹H NMR (DMSO-d₆) δ 7.55 (d, 2H, J=7.2 Hz),7.38 (t, 2 H, J=7.2 Hz), 7.27 (t, 1H, J=7.2 Hz), 7.05 (m, 3H), 6.38 (d,1H, J=8.0 Hz), 6.31 (s, 1H), 6.23 (d, 1H, J=7.9 Hz), 5.52 (s, 1H), 5.26(s, 2H), 2.92 (t, 2H, J=8.0 Hz), 2.58 (t, 2H, J=8.1 Hz). Anal. Calc. forC₂₁H₁₉N₃0.3H₂O: C, 75.33; H, 5.90; N, 12.55. Found: C, 75.46; H, 5.96;N, 12.35.

[0176] To a stirred solution of 3-(3-styryl4,5-dihydro-1H-indazol-6-yloxy)-phenylamine (50 mg, 0.15 mmol) andN,N-diisopropylethylamine (54 μl, 0.31 mmol) in 5 mL of CH₂Cl₂, wasadded benzoyl chloride (36 μl, 0.31 mmol). After 15 min, the reactionmixture was diluted with CH₂Cl₂ and washed sequentially with 0.5N HCl,saturated sodium bicarbonate solution and brine, dried (MgSO₄) andconcentrated under reduced pressure. To a stirred solution of theresidue in 1,4-dioxane was added2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (35 mg, 0.15 mmol).After 1 h, the reaction mixture was concentrated under reduced pressureand the residue was chromatographed on silica gel eluting hexanes/EtOAc(2:1). In this manner,N-[3-(2-benzoyl-3-styrl-1H-indazol-6-yloxy)-phenyl]-benzamide wasprepared as a rust colored solid (90 mg, ˜quantitative): ¹H NMR (CDCl₃)δ 8.13 (s, 1H), 8.02 (d, 2H, J=7.0 Hz), 7.94 (d, 1H, J=8.7 Hz), 7.74 (d,2H, J=6.8 Hz), 7.57-7.19 (m, 17H), 6.84 (d, 1H, J=8.3 Hz).

Example 4(b): N-[3-(3-Styryl-1H-indazol-6-yloxy)-phenyl]-acetamide

[0177]

[0178] Example 4(b) was prepared in a similar manner to that describedfor Example 4(a) above, except that acetic anhydride was used instead ofbenzoyl chloride in step (iv). ¹H NMR(DMSO-d₆) δ 13.08 (bs, 1H), 10.03(s, 1H), 8.22 (d, 1H, J=8.7 Hz), 7.72(d, 2H, J=7.3 Hz), 7.52 (s, 2H),7.44-7.27 (m, 6H), 7.01 (s, 1H), 6.96 (dd, 1H, J=8.7, 2.1 Hz), 6.78 (d,1H, J=6.9 Hz), 2.01 (s, 3H). Anal. Calc. for C₂₃H₁₉N₃O₂.0.25 H₂O: C,73.88; H, 5.26; N, 11.24. Found: C, 74.20; H, 5.57; N, 10.82.

Example 5(a): 5-Methyl-thiazole-2-carboxylic acid{3-(3-styryl-1H-indazol-6-yloxy)-phenyl]-amide

[0179]

[0180] A suspension of 5-methyl-thiazole-2-carboxylic acid{3-[1-(5-methyl-thiazole-2-carbonyl)-3-styryl-1H-indazol-6-yloxyl-phenyl}amide(57 mg, 0.10 mmol) and potassium carbonate (50 mg, 0.36 mmol) in MeOHwas stirred at 23° C. for 20 min. The solution was filtered, dilutedwith EtOAc and washed with brine (2×). The organic layer was dried(MgSO₄) and concentrated under reduced pressure. In this manner,5-methyl-thiazole-2-carboxylic acid{3-(3-styryl-1H-indazol-6-yloxy)-phenyl]-amide was prepared as a tansolid in 47% yield.: ¹H NMR (DMSO-d₆) δ 13.00 (s, 1H), 10.80 (s, 1H),8.23 (d, 1H, J=8.8 Hz), 7.79 (s, 2H), 7.71 (t, 2H, J=8.6 Hz), 7.53 (s,2H), 7.41-7.27 (m, 5H), 7.04 (s, 1H), 7.00 (d, 1H, J=8.7 Hz), 6.89 (d,1H, J=8.5 Hz), 2.54 (s, 3H). Anal. Calc. for C₂₆H₂₀N_(4l O) ₂S .1.15H20:C, 65.98; H, 4.75; N, 11.84; S, 6.78. Found: C, 65.99; H, 4.71; N,11.58; S, 6.76.

[0181] The starting material was prepared as follows:

[0182] 3-(3-Styryl-4, 5-dihydro-1H-indazol-6-yloxy)-phenylanine wasconverted to 5-methyl-thiazole-2-carboxylic acid{3-[1-(5-methyl-thiazole-2-carbonyl)-3-styryl-1H-indazol-6-yloxyl-phenyl}amide by treatment with 5-methyl-thiazole-2-carboxylic acid and HATU(o-(2-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) in DMF and analogous work-up, DDQ treatment andisolation to Example 4(a), step (iv) (50% yield): ¹H NMR(DMSO-d₆) δ10.85 (s, 1H), 8.45 (d, 1H, J=9.8 Hz), 8.24 (m, 3H), 7.99-7.62 (m, 6H),7.54-7.34 (m, 5H), 6.96 (d, 1H, J=8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).

Example 5(b):3-Methyl-N-[3-(3-styryl-lh-indazol-6-yloxy)-phenyl]-benzamide

[0183]

[0184] Example 5(b) was prepared in a similar manner to that describedfor Example 5(a) above, except that m-tolylchloride was used in place of5-methyl-thiazole-2-carboxylic acid and HATU in step (i). ¹H NMR(DMSO-d₆) δ 13.04 (s, 1H), 10.28 (s, 1H), 8.23 (d, 1H, J=8.8 Hz),7.73-7.30 (m, 14 H), 7.05 (s, 1H), 6.99 (d, 1H, J=8.5 Hz), 6.87 (d, 1H,J=7.7 Hz), 2.38 (s, 3H). Anal. Caic. for C₂₉H₂₃N₃O₂ .0.2H₂O.0.2 hexanes:C, 77.78; H, 5.66; N, 9.01. Found: C, 77.80; H, 5.84; N, 8.93.

Example 6(a):N-(3-{3-[2-(4-Chloro-phenyl)-vinyl]-1H-indazol-6-yloxy}-phenyl)-benzamide

[0185]

[0186] Starting fromN-(3-{1-benzoyl-3-[2-(4-chloro-phenyl)-vinyl]-1H-indazol-6-yloxyl}-phenyl)-benzamide,the general procedure for example 5(a) was used to prepare the titlecompound as an off-white solid in 72% yield: ¹H NMR (DMSO-d₆) δ 13.07(s, 1H), 10.32 (s, 1H), 8.24 (d, 1H, J=8.8 Hz), 7.92 (d, 2H, J=7.1 Hz),7.76 (d, 2H, J=8.5 Hz), 7.59-740 (m, 10H), 7.05 (s, 1H), 7.00 (d, 1H,J=8.7 Hz), 6.87 (d, 1H, J=7.9 Hz). Anal. Calc. for C₂₈H₂₀CIN₃0₂ 0.4H₂00.15 hexanes; C, 71.41; H, 4.75; N, 8.65. Found: C, 71.62; H, 14.83; N,8.45.

[0187] The starting material was prepared as follows:

[0188] Starting with3-[3-(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone and3-(4-chloro-phenyl)-acryloyl chloride (prepared as described below), thegeneral procedure for Example 4(a), step (ii) was employed. The productwas used without purification in the hydrazine cyclization procedure,Example 4(a) step (iii), to give3-{3-[2-(4-chloro-phenyl)-vinyl]4,5-dihydro-1H-indazol-6-yloxyl}-phenylamine as a yellow solid in 30% yield. ¹H NMR(DMSO-d₆) δ 12.45 (s, 1H), 7.58 (d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5Hz), 5.52 (s, 1H), 5.26 (s, 2H), 2.92 (t, 2H, J=8.0 Hz), 2.58 (t, 2H,J=8.0 Hz). Anal. Calc. for C₂₁H₁₈CIN₃O.0.75H₂O: C, 66.84; H, 5.21; N,11.14. Found: C, 66.73; H, 4.89; N, 11.01.

[0189] 3-(4-chloro-phenyl)-acryloyl chloride was prepared as follows: Toa stirred suspension of 4-chloro-trans-cinnamic acid (2.51 g, 13.77mmol) in benzene was added thionyl chloride (1.1 mL, 15.14 mmol) and acatalytic amount of DMAP. The reaction mixture was heated at reflux for1.5 h. The volatile materials were removed under reduced pressure. Thewhite residue was dissolved in Et₂O and concentrated again under reducedpressure, to give 3-(4-chloro-phenyl)-acryloyl chloride (2.78 g,quantitative) as a white solid: ¹H NMR (CDCl₃) δ 7.81 (d, 1H, J=15.6Hz), 7.54 (d, 2H, J=8.6 Hz), 7.44 (d, 2H, J=8.6 Hz), 6.65 (d, 1H, J=15.6Hz).

[0190]3-{3-[2-(4-Chloro-phenyl)-vinyl]4,5-dihydro-1Hindazol-6-yloxyl}-phenylaminewas converted intoN-(3-{1-benzoyl-3-[2-(4-chloro-phenyl)-vinyl]-1H-indazol-6-yloxyl}-phenyl)-benzamide by the procedure described in Example 4(a), step (iv)(85% yield). 1H NMR (DMSO-d₆) δ 10.37 (s, 1H), 8.43 (d, 1H, J=8.8 Hz),8.00-7.39 (m, 21H), 7.34 (d, 1H, J=8.8 Hz), 6.93 (d, 1H, J=8.8 Hz).

Example 6(b):N-{3-[3-(2-Indolyl)-1H-indazol-6-yloxy]-phenyl}-3-methyl-benzamide

[0191]

[0192] Example 6(b) was prepared in a similar manner to that describedfor Example 6(a) above, except that 1-SEM-indazole-2-carboxylic acid wasused in step (i) in place of 4-chlor-trans-cinnamic acid. ¹H NMR(DMSO-d₆) δ 13.19 (s, 1H), 11.59 (s, 1H), 10.29 (s,1H), 8.23 (d, 1H,J=8.7 Hz), 7.73-7.38 (m, 9H), 7.12 (s,1H), 7.03 (d, 2H, J =7.3 Hz), 6.88(d, 1H, J=7.8 Hz), 2.38 (s, 1H). HRMS [m+H]/z Calc'd: 459.1821, found459.1836.

Example 7: ³-(Styryl-1H-indazol-6-yloxy)-phenylamine

[0193]

[0194] A suspension of3-(3-styryl-4,5-dihydro-1H-indazol-6-yloxy)-phenylamine (75 mg, 0.23mmol) and 90 mg of 5% palladium on carbon (Pd/C) was heated at 155° C.After 4 h, more 5% Pd/C (39 mg) was added. After 22 h, more 5%Pd/C (30mg) was added. The reaction mixture was filtered while hot after 26 h.The catalyst was washed and the filtrate concentrated under reducedpressure. The residue was chromatographed on silica elutinghexanes/EtOAc (1:1). The appropriate fractions were concentrated andtriturated with CH₂Cl₂/hexanes to give the title compound as anoff-white solid (20 mg, 27%): ¹H NMR (DMSO-d₆) δ 8.16 (d, 1H, J=8.5 Hz),7.71 (d, 2H, J=6.7 Hz), 7.50 (s, 2H), 7.40 (t, 2H, J=7.0 Hz), 7.30 (d,1H, J=6.5 Hz), 7.06-6.92 (m, 3H), 6.35 (d, 1H, J=8.3 Hz), 6.23 (s, 2H),5.26 (s, 2H). Anal. Calc. for C₂₁H₁₇N₃O.0.15CH₂Cl₂: C, 74.69; H, 5.13;N, 12.36. Found: C, 74.64; H, 5.23; N, 12.25.

Example 8(a): 3-(E-stryl)-6-phenoxy-1H-indazole

[0195]

[0196] A suspension of 3-(E-styryl)-6-phenoxy-4,5-dihydro-1H-indazole(200 mg. 0.64 mmol) and 5% Pd/C (200 mg) in 10 mL of tetralin was heatedat 155° C. for 18 h. The catalyst was removed by filtering the hotsolution and washed with THF, EtOAc and MeOH. The filtrate wasconcentrated under reduced pressure and the residue was chromatographedon silica gel eluting hexanes/EtOAc (2:1) to provide3-(E-styryl)-6-phenoxy-1H-indazole as an off-white solid (110 mg, 55%).¹H NMR (DMSO-d₆) δ 6.96 (s, 2H), 7.10 (d, 2H, J=7.7 Hz), 7.20 (t, 1H,J=7.1 Hz), 7.30 (t, 1H, J=7.1 Hz), 7.44 (m, 6H), 7.71 (d, 2H, J=7.5 Hz),8.20 (d, 1H, J=9.2 Hz), 12.90 (s, 1H). Anal. Calc. for C₂₁H₁₆N₂O.0.1H₂O:C, 80.28; H, 5.20; N, 8.92. Found: C, 80.20; H, 5.21; N,8.93.

[0197] The starting material was prepared as follows:

[0198] (i) To a stirred solution of 3-chloro-cyclohex-2-enone (3.00 g,23.0 mmol) and phenol (2.16 g, 23.0 mmol) in 25 mL of acetone was addedpowdered, anhydrous K₂CO₃ (3.81 g, 27.6 mmol). After refluxing for 18 h,the mixture was cooled and filtered. The filtrate was concentrated underreduced pressure and chromatographed on silica gel eluting withhexanes/EtOAc (4:1) to give 3-phenoxy-cyclohex-2-enone as a white solid:¹H NMR (CDCl₃) δ 2.10 (quint, 2H, J=6.3 Hz), 2.40 (t, 2H, J=6.2 Hz),2.68 (t, 2H, J=6.3 Hz), 5.14 (s,1H), 7.05 (d, 2H, J=7.5 Hz), 7.26 (t,1H, J=7.3 Hz), 7.41 (t, 2H, J=7.6 Hz).

[0199] (ii) A solution of 3-phenoxy-cyclohex-2-enone (301 mg, 1.6 mmol)in 1 mL of THF was added to a stirred solution of 1.0 M solution oflithium bis(trimethylsilyl)amide in THF (3.2 mL) at −78° C. After 15min, cinnamoyl chloride (266 mg, 1.6 mmol) was added all at once. After15 min, the reaction mixture was poured into 0.5 N HCI and extractedwith EtOAc (2×). The combined organic layers were washed with saturatedNaCl solution, dried (MgSO₄), filtered, and concentrated under reducedpressure. Chromatography of the residue with 4:1 hexanes/ethyl acetateas eluant provided 220 mg (43%) of3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-enone as a yellow solid (220mg, 43%): 1H NMR (CDCl₃) (enol form) δ 2.66 (t, 2H, J=7.2 Hz), 2.84 (t,2H, J=7.1 Hz), 5.11 (s, 1H), 6.86 (d, 1H, J=15.6 Hz), 7.02 (d, 2H, J=8.1Hz), 7.20 (m,2H), 7.28-7.38 (m, 3H). HRMS M+H+calc: 319.1334, found319.1340.

[0200] (iii) To a stirred solution of3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-enone (1.13 g, 3.55 mmol) in20 mL of HOAc/EtOH(1:1) was added hydrazine monohydrate (.21 mL, 4.3mmol). The reaction was heated at 70° C. for 3 h, cooled and pouredcautiously into saturated Na HCO₃ solution and extracted with EtOAc(2×). The combined organic layers were washed with saturated NaCIsolution, dried (MgSO₄) and concentrated under reduced pressure. Theresidue was chromatographed on silica gel eluting hexanes/EtOAc (2:1) togive 6-phenoxy-3-styryl-4,5-dihydro-1H-indazole (3) as an off-whitesolid (406 mg, 36%): ¹H NMR (DMSO-d₆) δ 2.64 (t, 2H, J=8.0 Hz), 2.95 (t,2H, J=8.0 Hz), 5.46 (s,1H), 7.04 (AB, 2H, J=16.8 Hz), 7.15 (d, 2H, J=8.1Hz), 7.25 (m, 2H), 7.42 (m, 4H), 7.55 (d, 2H, J=7.7 Hz), 12.44 (s, 1H).Anal. Calc. for C₂H₁₈N₂O.0.2H₂O: C, 79.32; H, 5.83, N, 8.81. Found: C,79.36; H, 5.85; N, 8.84.

Example 8(b): 3-(E-styryl)-6-[4-(methoxymethoxy)phenoxy]-1H-indazole

[0201]

[0202] Example 8(b) was prepared in a similar manner to that describedfor Example 8(a) above, except that 4-(methoxymethoxy)phenol was used inplace of phenol in step (i). ¹H NMR (DMSO-d₆) δ 12.90 (s, 1H), 8.17 (d,1H, J=8.8 Hz), 7.71 (d, 2H, J=7.6 Hz), 7.50 (s, 3H), 7.41 (t, 2H, J=7.6Hz), 7.31 (d, 1H, J=7.4 Hz), 7.10 (s, 3H), 6.95 (dd, 1H, J=8.8, 1.9 Hz),6.84 (s, 1H), 5.20 (s, 2H), 3.42 (s, 3H). Anal. Calc. for C₂₃H₂₀N₂O₃: C,74.17; H, 5.41, N, 7.52. Found: C, 74.21; H, 5.59; N, 7.46.

Example 8(c): 3-(E-styryl)-6-phenylsulfanyl-1H-indazole

[0203]

[0204] Example 8(c) was prepared in a similar manner to that describedfor Example 8(a) above, except that thiophenol was used in step (i) inplace of phenol. ¹H NMR (DMSO-d₆) δ 7.29 (d, 1H, J=8.5 Hz), 7.45-7.59(m, 9H), 7.67 (s, 2H), 7.86 (d, 2H, J=7.2 Hz), 8.35 (d, 1H, J=8.5 Hz),13.30 (s, 1H). Anal. Calc. For C₂₁H₁₆N₂S 0.25H₂O: C, 75.76; H, 5.00; N,8.41; S, 9.63. Found: C, 75.79; H, 4.99; N, 8.16; S, 9.63.

Example 8(d): 6-(3-Bromo-phenoxy)-3-styryl-1H-indazole

[0205]

[0206] Example 8(d) was prepared in an analogous manner to thatdescribed for Exanple 8(a) above, except that 3-bromophenol was used instep (i) in place of phenol. ¹H NMR (DMSO-d₆) δ 13.08 (s, 1H), 8.23 (d,1H, J=8.8 Hz), 7.72 (d, 2H, J=7.3 Hz), 7.53 (s, 2H), 7.43-7.35 (m, 4H),7.30 (t, 2H, J=7.2 Hz), 7.11 (d, 1H, J=7.2 Hz), 7.09 (s, 1H), 6.98 (d,1H, J=8.8 Hz). Anal. Calc. for C₂₁H₁₅BrN₂O: C, 64.46; H, 3.86; Br,20.42; N, 7.16. Found: C, 64.31; H, 3.99; Br, 20.52; N, 7.11.

Example 9 (a): 3-(E-styryl)-6-[3-hydroxyphenoxy]-1H-indazole

[0207]

[0208] To a stirred solution of3-(E-styryl)-6-[3-(methoxymethoxy)phenoxy]-1H-indazole (50 mg, 0.13mmol) in 5 mL CH₂C 12 at -25° C. was added trimethylsilylbromide (75 μl,0.57 mmol). After 1.5 h, saturated NaHCO₃ solution was added and theproduct was extract with EtOAc (2×). The combined organic layers werewashed with saturated NaCl solution, dried (MgSO₄) and concentratedunder reduced pressure. The residue was chromatographed on silica geleluting hexanes/EtOAc (1:1) to give, after trituration withCH₂Cl₂/hexanes, 3-(E-styryl)-6-[3-hydroxyphenoxy]-1H-as an off-whitesolid (22 mg, 50%): ¹H NMR (DMSO-d₆) δ 6.37 (s, 1H), 6.43 (d, 1H, J=8.1Hz), 6.50 (d, 1H, J=8.1 Hz), 6.88 (d, 1H, J=8.8 Hz), 6.92 (s, 1H), 7.12(t, 1H, J=8.1 Hz), 7.24 (t, 1H, J=7.3 Hz), 7.31 (t, 2H, J=7.6 Hz), 7.44(s, 2H), 7.64 (d, 2H, J=7.5 Hz), 8.12 (d, 1H, J=8.7 Hz), 9.54 (s,1H),12.92 (s, 1H). Anal. Calc. For C₂₁H₁₆N₂O₂O.0.3H₂O: C, 75.57; H, 5.01; N,8.39. Found: C, 75.74; H, 5.11; N, 8.25.

[0209] The starting material,3-(E-styryl)-6-[3-(methoxymethoxy)phenoxy]-1H-indazole, was prepared asdescribed in Example 8(b).

[0210]¹H NMR (CDCl₃) δ 3.42 (s, 3H), 5.10 (s, 2H), 6.64 (d, 1H, J=8.2Hz), 6.72 (s, 1H), 6.80 (d, 1H, J=8.3 Hz), 6.98 (s, 1H), 7.00 (d, 1H,J=8.8 Hz), 7.19-7.38 (m, 5H), 7.53 (m, 3H), 7.92 (d, 1H, J=8.9 Hz).Anal. Calc. For C₂₃H₂oN₂0₃: M+H+: 373.1552, found 73.1546

Example 9(b): 3-(E-styry1)-6-[4-hydroxyphenoxy]-1H-indazole

[0211]

[0212] Example 9(b) was prepared like Example 9(a) above, except that3-E-styryl)-6-[4-(methoxymethoxy)phenoxy]-1H-indazole was used in placeof 3-(E-styryl)-6-[3-(methoxymethoxy)phenoxy]-1H-indazole. ¹H NMR(DMSO-d₆) δ 12.95 (s, 1H), 9.58 (s, 1H), 8.33 (d, 1H, J=9.0 Hz), 7.89(d, 2H, J=7.1 Hz), 7.68 (s, 1H), 7.58 (t, 1H, J=7.3 Hz), 7.48 (d, 1H,J=7.3 Hz), 7.24 (s, 1H), 7.13 (m, 3H), 6.99 (d, 2H, J=8.8 Hz). HRMS[m+H]/z Calc'd: 329.1290. Found: 329.1293. Anal. Calc. forC₂₁H₁₆N₂O₂.0.35H₂O: C, 75.36; H, 5.03; N, 8.37. Found: C, 75.35; H,5.22; N, 8.24.

Example 10: 6-(1-Phenyl-vinyl)-3-styryl-1H-indazole

[0213]

[0214]6-(1-Phenyl-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole(16.2 mg, 0.0358 mmol) was dissolved in THF (0.6 mL) and was treatedwith tetrabutylammonium fluoride (IBAF, 1M in THF, 0.6 mL). The mixturewas heated to 60° C. under argon for 4 h. The mix was cooled,neutralized with excess saturated sodium bicarbonate and the organicmaterial was extracted into ethyl acetate and concentrated. This mix of3 compounds (by TLC visualization) was treated with THF-water-TFA(1:1:2, 4 mL) for 30 min. The mix was diluted with toluene (20 mL),concentrated, neutralized with excess saturated sodium bicarbonate, andthe organic material was extracted into ethyl acetate. The organicmaterial was dried over sodium sulfate, decanted and concentrated.Purification by silica gel chromatography (2:8 ethyl acetate-hexane)gave 6-(1-Phenyl-vinyl)-3-styryl-1H-indazole (4.6 mg, 40%): R_(f) sm0.62, p 0.24 (ethyl acetate-hexane 3:7); ¹H NMR (300 MHz, CDCl₃) δ 7.99(d, 1H, J=8.5 Hz), 7.60-7.25 (m, 14H), 5.58 (d, 1H, J=1.1 Hz), 5.56 (d,1H, J=1.1 Hz); HRMS (FAB) [m+H]/z Calc'd 323.1548, Found 323.1545.

[0215] The starting material was prepared as follows:

[0216] 6-Iodoindazole was converted to 3,6-diiodoindazole (82%) asdescribed in Example 1(a), step (v): ¹H NMR (300 MHz, CDCl₃) δ 10.3 (bs,1H),7.90 (s, 1H), 7.52 (dd, 1H,J=1.2, 8.5 Hz), 7.24 (d, 1H,J=8.5 Hz).

[0217] 3,6-Diiodoindazole (755 mg, 2.04 mmol) was added to 50% KOH (2.5g in 2.5 mL water) at 0° C. and dichloromethane (4 mL) was added. Tothis mixture was added tetrabutylammonium bromide (TBABr, 6.6 mg, 0.02mmol, 0.01 equiv) and 2-(trimethyl-silanyl)-ethoxymethyl chlorlde(SEM-Cl, 397 μL, 2.24 mmol, 1.10 equiv) was added dropwise over a 3 minperiod. The mixture was stirred rapidly at 0° C. for 1.5 h. Water (20mL) and dichloromethane (20 mL) were added and the organic material wasseparated, dried over sodium sulfate and concentrated. Silica gelchromatography (5% ethyl acetate in hexane; 150 mL silica) gave 2isomeric compounds (1-SEM, 763 mg, 75%; and 2-SEM, 105 mg, 10%): R_(f)sm 0.08, p 0.34 and 0.27 (ethyl acetate-hexane 1:9); ¹H NMR (300 MHz,CDCl₃) δ 8.0 (s, 1H), 7.55 (d, 1H, J=8.5 Hz), 7.24 (d, 1H, J=8.5 Hz),5.69 (s, 2H), 3.58 (t, 2H J=8.2 Hz), 0.90 (t, 2H, J=8.2 Hz), -0.1 (s,9H).

[0218] 1-Bromostyrene (26 μL, 0.20 mmol, 2.0 equiv) was dissolved in THF(0.75 mL), cooled to −78° C. and was treated with t-BuLi (235 lL, 0.40mmol, 1.70 M, 4.0 equiv). The mixture was allowed to warm to 42° C. for10 min and was added to freshly dried zinc chloride (34 mg, 0.25 mmol,2.5 equiv). The resulting solution was allowed to warm to 23° C. withstirring for 25 min. This mix was added to a mixture of neat3,6-Diiodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (50 mg,0.10 mmol, 1 equiv) and Pd(PPh₃)₄ (5 mg, 0.004 mmol, 0.04 equiv). After10 min the reaction was determined to be complete by TLC monitoring andwas quenched with saturated sodium bicarbonate. Organic material wasextracted into ethyl acetate, dried over sodium sulfate and concentratedunder reduced pressure. Silica gel chromatography (5:95 ethylacetate-hexane) provided3-Iodo-6-(1-phenyl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole(33.1 mg, 70 %): R_(f) sm 0.39, p 0.36 (ethyl acetate-hexane 1:9); ¹HNMR (300 MHz, CDCl₃) δ 7.50 (s, 1H), 7.42 (d, 1H, J=8.4 Hz), 7.33 (m,5H), 7.22 (dd, 1H, J=1.2, 8.4 Hz), 5.68 (s, 2H), 5.59 (d, 1H, J=1.0 Hz),5.57 (d, 1H, J=1.0 Hz), 3.58 (t, 2H, J=8.2 Hz), 0.88 (t, 2H, J=8.2 Hz),-.09 (s, 9H); HRMS (FAB) [m+H]/z Calc'd 477.0859, found 477.0866.

[0219] Preparation of6-(1-Phenyl-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole:E-2-Bromostyrene (23 μL, 0.174 mmol, 2.5 equiv) was dissolved in THF(1.0 mL) and was cooled to −78° C. t-BuLi (205 μL, 0.348 mmol, 5.00equiv) was added and the mixture was warmed to 42° C. for 7 min to givea deep red mixture. The solution was added to freshly dried zincchloride (29 mg, 0.209 mmol, 3.00 equiv) via cannula and the mix wasallowed to warm to 23° C. with stirring for 20 min. This solution wasadded to a neat mixture of3-Iodo-6-(1-phenyl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1Hindazole(33.1 mg, 0.0696 mmol, 1.0 equiv) and Pd(PPh₃)₄ (4 mg, 0.0035 mmol, 0.05equiv) at 23° C. via cannula. This solution was allowed to stir for 15min and was treated with saturated sodium bicarbonate and extracted withethyl acetate. The organic material was dried over sodium sulfate,decanted and concentrated. Purification by silica gel chromatographyusing two columns (5:95 ethyl acetate-hexane; 12 mL silica: and 1:99ethyl acetate-benzene; 12 mL silica) gave6-(1-Phenyl-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1Hindazole (16.2 mg, 51%): R_(f) sm 0.38, p 0.29 (ethyl acetate-hexane1:9); ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, 1H, J=8.4 Hz), 7.62-7.22 (m,14H), 5.71 (s, 2H), 5.57 (s, 2H), 3.60 (t, 2H, J=8.2 Hz), 0.90 (t, 2H,J=8.2 Hz), -.08 (s, 9H); HRMS (FAB) [m+H]/z Calc'd 453.2362, Found453.2354.

Example 11: N-Methyl-N-(3-styryl-1H-indazol-6-yl)-benzene-1,3-diamine

[0220]

[0221] ToN-methyl-N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine(237 mg, 0.5 mmol) was added IM TBAF in THF (10.1 mL, 10.1 mmol),followed by ethylenediamine (0.34 mL, 5.04 mmol, 10 equiv). Theresulting mixture was heated to 70° C. for 5 h. The reaction was thenquenched with saturated NaHCO3 (10 mL) and extracted 3×35 mL EtOAc. Thepooled EtOAc phase was washed 5×20 mL H₂O, then brine (20 mL), driedwith Na₂SO₄, decanted and concentrated under reduced pressure to a foam.The crude material was purified by silica gel chromatography (9:1dichloromethane/ethyl acetate) to giveN-methyl-N-(3-styryl-1H-indazol-6-yl)-benzene-1,3-diamine as a foam (120mg, 70% yield). R_(f) sm 0.73, Rfp 0.27 (dichloromethane:ethylacetate7:3); ¹³C NMR (75 MHz, CDCl₃) δ 150.3, 148.8, 147.5, 147.5, 143.9,143.4, 137.5, 131.1, 130.3, 129.3, 128.9, 128.2, 127.9, 126.7, 121.0,120.5, 117.0, 116.0, 112.6, 109.8, 109.0, 98.3, 40.7; LCMS (ESI) [M+H]/zCalc'd 341, Found 341. Anal. Calc'd: C, 77.62; H, 5.92; N, 16.46. Found:C, 76.16; H, 5.88; N, 15.95.

[0222] Starting material prepared as follows:

[0223] 6-nitro-1H-indazole was converted to 3-Iodo-6-nitro-1H-indazoleas described in Example 1(a), step (v) (50.6 g, 87%): FTIR (KBr) 3376,3076, 2964, 2120, 1739, 1626, 1526, 1439, 1294, 1128, 954 cm-1;H NMR(300 MHz, CDCl₃) δ 8.28 (s, 1H), 8.05 (s, 1H), 7.66 (d, 1H, J=8.13 Hz),7.45 (dd, 1H, J=8.33, 1.38 Hz), 7.17 (d, 1H, J=1.01 Hz), 7.14 (s, 1H),7.03 (d, 1H, J=8.04 Hz), 6.89 (s, 2H), 3.82 (s, 3H), 2.55 (s, 6H), 2.21(s, 3H) 1.32 (s, 9H). MS (FAB) [M+H]/z Calc'd 311, Found 311. Anal.Calc'd: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.41; H, 5.98; N, 8.79.

[0224] 3-Iodo-6-nitro-1H-indazole was converted to6-Nitro-3-iodo-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole asdescribed in Example 10, step (ii) (10.2 g, 81% yield): mp 58° C. Anal.Calc'd: C, 37.24; H, 4.33; N, 10.02. Found: C, 37.21; H, 4.38; N, 10.00.

[0225] To6-nitro-3-iodo-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (11.0 g,26.1 mmol), styryl boronic acid (4.64, 31.4 mmol), and Pd(PPh3)4 (1.25g, 1.08 mmol) under an atmosphere of argon was added toluene (192 mL),MeOH (4 mL) and 2N NaOH (aq) (32.6 mL, 65.3 mmol). The resultingheterogeneous mixture was heated to 90° C. After 8 h the reaction wasdiluted with EtOAc (150 mL) and water (50 mL), the phases were separatedand the organic was extracted 2×50 mL EtOAc. The pooled organic phasewas washed with brine (50 mL), then dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The crude reaction was purified bysilica gel chromatography (1:9 EtOAc:hexane) to give6-nitro-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as ayellow solid (7.65 g, 74%): ¹³C NMR (75 MHz, CDCl₃) 8 148.3, 145.0,141.3, 138.1, 134.2, 130.5, 129.9, 129.8, 129.5, 128.1, 127.4,123.2,119.8, 117.8, 108.2, 79.7, 68.5, 19.2, 0.0; MS (FAB) [M+Na]/zCalc'd 418, found 418. Anal. Calc'd: C, 63.77; H, 6.37; N, 10.62. Found:C, 64.04; H, 6.29; N, 10.56.

[0226]6-Nitro-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (8.1g, 20.5 mmol) was dissolved in DMF (75 mL) at 23° C. under an atmosphereof argon. SnCI2 (12.9 g, 67.7 mmol) was added followed by water (1.7 mL,92.2 mmol) and the resulting mixture was heated to 50° C. After 4 h, 3NNaOH (45 mL, 135 mmol) was added followed by EtOAc (100 mL). Theresulting emulsion was filtered hot through Celite and the bed of Celitewas washed with hot EtOAc (3×100 mL). The filtrate was concentratedunder reduced pressure, the residue was dissolved in EtOAc, washed withbrine, dried with Na₂SO₄, filtered and concentrated under reducedpressure to give a solid. The crude material was purified by silica gelchromatography (2:87:3 ethyl acetate:hexane), to give3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine asa yellow solid (5.1 g, 68% yield). MS (FAB) [M+H]/z Calc'd 366, found366.

[0227] To3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine(1.1 g, 3 mmol, m-nitro-iodobenzene (0.9 g, 3.6 mmol), BINAP (0.07 g,0.133 mmol), Pd2(dba)3 (34 mg, 0.0375 mmol) and Cs2CO3 (1.37 g, 4.2mmol) under an atmosphere of argon was added toluene (6 mL). Theresulting heterogeneous mixture was heated to 80° C. After 46 h thereaction was cooled to 23° C. diluted with ethyl acetate (EtOAc) (20 mL)and filtered. Water (5 mL) was added, the phases were separated, and theorganic was extracted 2×50 mL EtOAc. The pooled organic material waswashed with brine, then dried with Na₂SO₄, filtered and concentratedunder reduced pressure. The crude reaction was purified by silica gelchromatography (eluting with 9:1 hexane:EtOAc) to give(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amineas a yellow solid (7.65 g, 74%): TLC (Hexane:EtOAc 7:3) Rf sm 0.16,R_(f) p 0.30 (ethyl acetate:hexane 3:7); FTIR (KBr) 3391, 3059, 2952,2894, 1614, 1530, 1483, 1346, 1248, 1076, 836, 734 cm-1;¹H NMR (300 MHz,CDCl₃) δ 7.86 (s, 1H), 7.83 (s, 1H), 7.65 (dt, 1H, J=2.21, 5.13 Hz),7.15-7.41 (m, 5H), 6.93 (dd, 1H, J=1.87, 8.67 Hz), 5.56 (s, 2H), 3.51(t, 2H, J=8.17 Hz), 0.81 (t, 2H, J=7.96 Hz), -0.15 (s, 9H); ¹³C NMR (75MHz, CDCl₃) δ 149.6, 144.8, 143.5, 142.4, 140.9, 137.3, 131.8, 130.3,129.0, 128.2, 126.7, 122.8, 122.6, 120.1, 119.3, 116.1, 115.6, 111.4,98.5, 77.9, 66.7, 18.0,-1.2; MS (ESI) [M+H]/z Calc'd 487, found 487.Anal. Calc'd: C, 66.64; H, 6.21; N, 11.51. Found: C, 66.91; H, 6.21; N,11.44.

[0228] To(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine(434 mg, 0.89 mmol) in THF (5 mL) cooled to −5° C. under an atmosphereof argon, was added dimethylsulfate (0.42 mL, 4.5 mmol) followed byLiHMDS (IM in THF) (1.8 mL, 1.8 mmol). After 20 min the reaction wasquenched with saturated NH₄Cl (aq) (2 mL), then extracted 3×20 mL EtOAc.The pooled organic material was washed with brine (10 mL), dried withNa₂SO₄, decanted and concentrated under reduced pressure. Purificationby silica gel chromatography (eluting with hexane:EtOAc 9:1) gavemethyl-(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine,as an oil (367 mg, 82%): TLC (Hexane:EtOAc 7:3) R_(f) sm 0.29, Rfp 0.39(ethyl acetate: hexane 3:7); FTIR (KBr)2951, 2894, 1611, 1528, 1485,1348, 1248, 1077 cm-1;¹HNMR(300 MHz, CDCl₃) δ 7.99 (d, 1H, J=8.67 Hz)7.77 (t, 1H, J=2.25 Hz), 7.72 (dd, 1H, J=0.79, 2.09 Hz), 7.60, (d, 2H,J=7.22 Hz), 7.26-7.54 (m, 7H), 7.19 (dd, 1H, J=0.78, 2.41 Hz) 7.07 (dd,1H, J=1.85, 8.69 Hz), 5.70 (s, 2H), 3.63 (t, 2H, J=8.10 Hz), 3.48 (s,3H), 0.92 (t, 2H, J=8.10 Hz), -0.04 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ150.2, 149.6, 147.1, 143.5, 142.5, 137.3, 131.9, 129.8, 129.0, 128.2,126.8, 123.1, 122.6, 120.2, 120.0, 119.7, 114.4, 111.4, 104.5, 78.0,66.8, 41.1, 18.0,-1.2; LCMS (ESI) [M+H]/z Calc'd 501, Found 510.

[0229]Methyl-(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-aminewas converted toN-methyl-N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine as described in Example 11, step (iv). R_(f) sm0.55, R_(f) p 0.31 (ethyl acetate:hexane 3:7); FTIR (thin film) 3455,3360, 2951, 2893, 1621, 1601, 1494, 1449, 1249, 1074 cm⁻¹;⁻¹H NMR (300MHz, CDCl₃) δ 7.81 (d, 1H, J=8.8 Hz) 7.58 (d, 2H, J=7.21 Hz), 7.26-7.50(m 5H), 7.12 (t, 1H, J=7.93 Hz), 7.01 (d, 1H, J=1.73 Hz), 6.95 (dd, 1H,J=1.99, 8.85 Hz), 5.67 (s, 2H), 3.63 (t, 2H, J=8.12 Hz), 3.38 (s, 3H),0.93 (t, 2H, J=8.13 Hz), −0.04 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 150.3,149.0, 147.7, 143.4, 143.0, 137.6, 131.3, 130.4, 128.9, 128.0, 126.7,121.2, 120.6, 117.3, 117.0, 113.1, 110.1, 109.3, 97.5, 77.8, 66.6, 41.0,18.0,-1.2; LCMS (ESI) [M+H]/z Calc'd 471, Found 471.

Example 12(a):N-{3-[Methyl-(3-styryl-1H-indazol-6-yl)-amino]-phenyl}-acetamide

[0230]

[0231]N-Methyl-N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine,prepared in Example 11 (34 mg, 0.041 mmol) was suspended in CH₂Cl₂ (0.5mL) at 23° C. under an atmosphere of argon. Pyridine (81 μl, 1.0 mmol),Ac₂O (94 μl, 1.0 mmol) and DMAP (cat.) were added. The reaction becamehomogeneous immediately. After 1 h, TLC analysis (CH₂Cl₂:EtOAc 4:1)indicated no starting material. The reaction was quenched with saturatedNaHCO₃(aq) (2 mL) then diluted with EtOAc (15 mL) and the organic phasewas washed with brine (3 mL), decanted and concentrated under reducedpressure to an oil. The oil was suspended in MeOH (2 mL) and K₂CO₃ (83mg, 0.6 mmol) was added. The resulting mixture was stirred at 23° C.under an atmosphere of argon. After 1 h, the reaction was diluted withEtOAc (15 mL) and the organic phase was washed with brine (3 mL),decanted and concentrated under reduced pressure. The crude material waspurified by semi-prep HPLC to giveN-{3-[methyl-(3-styryl-1H-indazol-6-yl)-amino]-phenyl}-acetamide (8.4mg, 22%). ¹H NMR (300 MHz, CDCl₃) δ 7.86 (d, 1H, J=8.68 Hz), 7.58 (d,1H, J=7.17 Hz), 7.16-7.45 (m, 7H), 7.15 (d, 1H, J=8.29 Hz), 6.98 (m,1H), 6.95 (d, 1H, J=1.92 Hz), 6.8 (dd, 1H, J=1.16, 8.05 Hz), 3.37 (s,3H), 2.14 (s, 3H). LCMS (ESI) [M+H]/z Calc'd 383, Found 383. Anal.Calc'd: C, 75.37; H, 5.80; N, 14.65. Found: C, 73.53; H, 6.01; N, 13.73.

Example 12(b):N-{3-[Methyl-(3-styryl-1H-indazol-6-yl)-amino]-phenyl}-benzamide

[0232]

[0233] Example 12(b) was prepared in a similar manner to that describedfor Example 12(a) above, except that benzoyl chloride was used insteadof acetic anhydride. LCMS (ESI) [M+H]/z Calc'd 475, found 475. Anal.Calc'd C (78.36), H (5.44), N (12.60). Found: C (76.57), H (5.50), N(12.12).

Example 12(c):{3-[Methyl-(3-styryl-1H-indazol-6-yl)-amino]-phenyl}-carbamic acidbenzyl ester

[0234]

[0235] Example 12(c) was prepared in a similar manner to that describedfor Example 12(a) above, except that carbobenzyloxy chloride was usedinstead of acetic anhydride. R_(f) sm 0.30, R_(f) p 0.57 (CH2C12:EtOAc8:2); LCMS (ESI+) [M+H]/z Calc'd 475 Found 475; Anal. Calc'd C (75.93),H (5.52), N (11.81) Found,C (75.60), H (5.96), N (10.75).

Example 12(d): 5-Methyl-thiazole-2-carboxylic acid{3-[methyl-(3-styryl-1H-indazol-6-yl)-amino]-phenyl}-amide

[0236]

[0237] To a solution ofN-methyl-N-(3-styryl-1H-indazol-6-yl)-benzene-1,3-diamine, prepared inExample 11, (26 mg, 0.075 mmol) and 5-methyl-thiazole-2-carboxylic acid(64 mg, 0.45 mmol) in DMF (0.375 mL) at 23° C. under an atmosphere ofargon was added HATU (171 mg, 0.45 mmol). After 1 h, TLC analysis(CH₂Cl₂:EtOAc 8:2) indicated no starting material. The reaction wasquenched with saturated NaHCO₃(aq) (2 mL) then diluted with EtOAc (15mL) and the organic phase was washed with brine (3 mL), decanted andconcentrated under reduced pressure. The oil was suspended in MeOH (2mL) and K2CO₃ (62 mg, 0.45 mmol) was added. The resulting mixture wasstirred at 23° C. under an atmosphere of argon. After 1 h TLC analysis(CH₂Cl₂:EtOAc 8:2) indicated no starting material. The reaction wasdiluted with EtOAc (15 mL) and the organic phase was washed with brine(3 mL), decanted and concentrated under reduced pressure to a solid. Thecrude material was purified by silica gel chromatography (eluting withCH₂Cl₂:EtOAc 85:15) to give the title compound after purification bysemi-prep. HPLC (9.9 mg, 28 %). R_(f) sm 0.25, R_(f) p 0.39(hexane:EtOAc 8:2); LCMS (ESI+) [M+H]/z Calc'd 466, found 466. Anal.Calc'd C (69.65), H (4.98), N (15.04) S (6.89). Found: C (69.24), H(5.35), N (13.97) S (5.95).

Example 13: N-[3-(3-Styryl-1H-indazol-6-ylamino)-phenyl]-benzamide

[0238]

[0239]N-(3-{3-Styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamino}-phenyl)-benzamidewas converted to N-[3-(3-styryl-1H-indazol-6-ylamino)-phenyl]-benzamideas described in Example 11. LCMS (ESI) [M+H]/z Calc'd 431, found 431.Anal. Calc'd: C, 78.12; H, 5.15; N, 13.01. Found: C, 77.06; H, 6.91; N,9.88.

[0240] The starting material was prepared as follows:

[0241](3-Nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine,prepared in Example 11, step (vi), was converted toN-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamineas described in Example 11, step (iv). LCMS (ESI) [M+H]/z Calc'd 457,found 457.

[0242] To a solution ofN-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine(91 mg, 0.2 mmol) and pyridine (0.081 mL, 1.0 mmol) in CH₂Cl₂ (0.5 mL)cooled to −5° C. under an atmosphere of argon was added benzoyl chloride(0.028 mL, 0.24 mmol). After 0.5 h the reaction was quenched withsaturated NaHCO₃(aq) then extracted 2×5 mL CH₂Cl₂. The pooled organicmaterial was washed with brine (5 mL), dried with Na₂SO₄, decanted andconcentrated under reduced pressure to give an oil. The crude materialwas purified by silica gel chromatography (eluting with hexane:EtOAc3:2) to giveN-(3-{3-Styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamino}-phenyl)-benzamide(108 mg, 96% yield). R_(f) sm 0.35, R_(f) p 0.44 (ethyl acetate:hexane1:1); FTIR (thin film) 3320, 2951, 2893, 1657, 1604, 1537, 1493, 1409,1303, 1248, 1074 cm-1; LCMS (ESI) [M+H]/z Calc'd 561, Found 561. Anal.Calc'd: C, 72.82; H, 6.47; N, 9.99. Found: C, 72.33; H, 6.39; N, 9.81.

Example 14: Methyl-phenyl-(3-styryl-1H-indazol-6-yl)-amine

[0243]

[0244]Methyl-phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl)-aminewas converted to methyl-phenyl-(3-styryl-1H-indazol-6-yl)-amine asdescribed in Example 11. MS (ESI) [M+H]/z Calc'd 326, found 326.

[0245] The starting material was made as follows:

[0246] To a solution of3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine(1.58 g, 4 mmol) in AcOH (14 mL), water (3 mL) and concentrated HCl(1.67 mL) cooled to 2° C. was added a solution of NaNO2 (304 mg, 4.4mmol) in water (0.5 mL) over 5 min. The resulting dark red solution wasstirred at 2° C. for 0.5 h, then a solution of KI (797 mg, 4.8 mmol) andI₂ (610 mg, 2.4 mmol) in water (1 mL) was added drop-wise so as to keepthe internal temperature below 5° C. After 2 h at 2° C. the reaction wasallowed to stir at 23° C. for 17 h. The reaction was quenched with 3 NNaOH (aq), diluted with EtOAc (50 mL) and H20 (15 mL), the phases wereseparated and the aqueous was extracted 2×15 mL EtOAc. The pooledorganic phase was washed 3×20 mL 5% NaHSO3, brine (15 niL), dried withNa₂SO₄, decanted and concentrated under reduced pressure. The crudereaction was purified by silica gel chromatography (eluting with 1:1hexane:EtOAc) to give6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as awhite solid (1.3 g, 68% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.03 (s, 1H),7.79 (d, 1H, J=9.0 Hz), 7.30-7.60 (m, 8H), 5.73 (s, 2H), 3.63 (t, 2H,J=6.0 Hz), 0.96 (t, 2H, J=6.0 Hz), 0.0 (s, 9); ¹³C NMR (75 MHz, CDCl₃) δ143.6, 142.4, 137.2, 132.1, 130.8, 129.0, 128.3, 126.8, 122.5, 122.4,119.6, 119.5, 92.9, 78.1, 66.9, 18.0,-1.2. Anal. Calc'd: C, 52.94; H,5.29; N, 5.88. Found: C, 52.66; H, 5.29; N, 5.74.

[0247]6-Iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole wasconverted tomethyl-phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amineas described in Example 11, step (v). R_(f) sm 0.35 R_(f) p 0.13(EtOAc:hexane 1:9); IR (KBr) 3031, 2951, 1625, 1595, 1498, 1449, 1326,1303, 1248, 1212, 1076, 835, 694 cm⁻¹; MS (ESI) [M+H]/z Calc'd 456,Found 456.

Example 15:N-[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-N-methyl-benzene-1,3-diamine

[0248]

[0249][3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-(3-nitro-phenyl)-aminewas converted toN-[3-(2-benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-N-methyl-benzene-1,3-diamineas described in Example 11, step (iv). LCMS (ESI) [M+H]/z Calc'd 385,found 385. Anal. Calc'd: C, 71.86; H, 5.24; N, 14.57. Found: C, 70.99;H, 5.60; N, 13.80.

[0250] The starting material was prepared as follows:

[0251] To a mixture of6-nitro-3-iodo-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (4.2 g,10 mmol), boronic acid (3.46 g, 15 mmol), and Pd(PPh3)4 (0.58 g, 0.5mmol) at 23° C. under an atmosphere of argon was added 1,4-dioxane (38mL) and 2N NaOH (aq) (12.5 mL, 25 mmol). The resulting mixture washeated to 90° C. After 2 h the reaction was diluted with EtOAc (100 mL)and water (70 mL), the phases were separated and the organic wasextracted 2×100 mL EtOAc. The pooled organic phase was washed with brine(20 mL) then dried with Na₂SO₄, filtered and concentrated under reducedpressure. The crude mixture was purified by silica gel chromatography(eluting with 9:1 hexane:EtOAc) to give3-(2-benzo[1,3]dioxol-5-yl-vinyl)-6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazoleas a yellow solid (4.15 g, 94% yield). FTIR (thin film) 2950, 2898,1523, 1501, 1483, 1446, 1344, 1249, 1080, 1043, 927 cm-¹; ¹H NMR (300MHz, CDCl₃) δ 8.56 (dd, 1H, J=0.68, 1.75 Hz), 8.14 (d, 1H, J=1.78 Hz),8.13 (d, 1H, J=0.67 Hz), 7.50 (d, 1H, 16.53 Hz), 7.25 (d, 1H, 16.52 Hz),7.18 (d, 1H, J=1.67 Hz), 7.07 (dd, 1H, J=1.65, 8.13 Hz), 6.88 (d, 1H,J=8.0 Hz), 6.05 (s, 2H), 5.84 (s, 2H), 3.66 (t, 2H, J=7.33 Hz), 0.97 (t,2H, J=7.24 Hz), 0.0 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) 8 148.5, 148.2,147.0, 143.9, 140.1, 132.7, 131.3, 126.1, 122.3, 121.9, 116.7, 116.5,108.7, 106.9, 105.7, 101.5, 78.4, 67.2, 17.9, −1.3; LCMS (ESI) [M+H]/zCalc'd 531, found 531.

[0252] 3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas converted to3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamineas described in Example 11, step (iv). ¹H NMR (300 MHz, CDCl₃) δ 7.73(d, 1H, J=8.56 Hz), 7.52 (d, 1H, J=16.57 Hz), 7.18 (d, 1H, J=16.56 Hz),7.10 (d, 1,H, J=1.49 Hz), 6.98 (dd, 1H, J=1.52, 8.06 Hz), 6.80 (d, 1H,J=8.01 Hz), 6.68 (d, 1H, J=1.44 Hz), 6.63 (dd, 1H, J=1.86, 8.57 Hz),5.95 (s, 2H), 5.59 (s, 2H), 3.59 (t, 2H, J=8.17 Hz), 0.91 (t, 2H, J=8.33Hz), 0.04 (s, 9H);¹³C NMR (75 MHz, CDCl₃) 8 148.3, 147.6, 146.4, 143.4,143.0, 132.0, 130.8, 122.0, 121.7, 118.8, 116.5, 113.1, 108.5, 105.5,101.3, 92.9,77.6, 66.3, 17.9,-1.3; LCMS (ESI) [M+H]/z Calc'd 410, found410.

[0253]3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylaminewas converted to{3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-(3-nitro-phenyl)-amineas described in Example 11, step (v). ¹³C NMR (75 MHz, CDCl₃) δ 150.8,149.7, 149.1, 146.0, 144.8, 143.6, 142.1, 133.1, 132.7, 131.6, 124.0,123.8, 123.1, 120.4, 119.5, 117.2, 116.8, 112.6, 109.9, 106.9, 102.6,99.7, 79.1, 67.9, 19.2, 0.0; MS (FAB) [M+H]/z Calc'd 531, found 531.Anal. Calc'd: C, 63.38; H, 5.70; N, 10.56. Found: C, 63.49; H, 5.76; N,10.42.

[0254]{3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-(3-nitro-phenyl)-arninewas converted to(3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methyl-(3-nitro-phenyl)-amineas described in Example 11, step (vi). FTIR (KBr) 2952, 2894, 1612,1529, 1503, 1489, 1446, 1407, 1348, 1306, 1251, 1077, 1039 cm-1; ¹³C NMR(75 MHz, CDCl₃) 8 150.1, 149.5, 148.4, 147.8, 147.0, 143.5, 142.4,131.8, 131.5, 129.8, 123.0, 122.49, 121.9, 120.1, 119.5, 118.2, 114.3,11.3, 108.7, 105.7, 104.5, 101.4, 78.0, 66.8, 41.0, 17.9,-1.2; MS (FAB)[M+H]/z Calc'd 545, found 545. Anal. Calc'd: C, 63.95; H, 5.92; N,10.29. Found: C, 62.63; H, 5.72; N, 9.62.

[0255] {3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl-3-methyl-(3-nitro-phenyl)-aminewas converted to[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-(3-nitro-phenyl)-amineas described in Example 11. LCMS (ESI) [M+H]/z Calc'd 415, found 415.Anal. Calc'd: C, 66.66; H, 4.38; N, 13.52. Found: C, 66.56; H, 4.48; N,13.35.

Example 16(a):N-(3-{[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-benzamide

[0256]

[0257] N-[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-H-indazol-6-yl]-N-methyl-benzene-1,3-diamine (prepared as described inExample 15) was converted toN-(3-([3-(2-benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-benzamide in the manner described in Example 12(a). LCMS (ESI)[M+H]/z Calc'd 489, Found 489. Anal. Calc'd: C, 73.76; H, 4.95; N,11.47. Found: C, 73.19; H, 5.09; N, 11.20.

Example 16(b):N-(3-{[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-3-methyl-benzamide

[0258]

[0259] Example 16(b) was prepared in a similar manner to that describedfor Example 16(a) above, except that m-toluyl chloride was used insteadof benzoyl chloride. LCMS (ESI) [M+H]/z Calc'd 504, found 504. Anal.Calc'd: C, 74.09; H, 5.21; N, 11.15. Found: C, 73.04; H, 5.84; N, 10.29.

Example 16(c):N-(3-{[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-3-dimethylamino-benzamide

[0260]

[0261] Example 16(c) was prepared in a similar manner to that describedfor Example 16(a), except that m-dimethylaminobenzoyl chloride was usedinstead of benzoyl chloride. LCMS (ESI) [M+H]/z Calc'd 532, found 532.Anal. Calc'd: C, 72.30; H, 5.50; N, 13.17. Found: C, 71.61; H, 5.80; N,12.75.

Example 16(d):N-(3-{[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-3-trifluoromethyl-benzamide

[0262]

[0263] Example 16(d) was prepared in a similar manner to that describedfor Example 16(a), except that m-trifluoromethylbenzoyl chloride wasused instead of benzoyl chloride. LCMS (ESI) [M+H]/z Calc'd 557, found557. Anal. Calc'd: C, 66.90; H, 4.17; N, 10.07. Found: C, 66.64; H,4.34; N, 9.82.

Example 16(e):3-Acetyl-N-(3-{[3-(2-benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-benzamide

[0264]

[0265] Example 16(e) was prepared in a similar manner to that describedfor Example 16(a), except that m-acetylbenzoyl chloride was used insteadof benzoyl chloride. LCMS (ESI) [M+H]/z Calc'd 531, found 531. Anal.Calc'd: C, 72.44; H, 4.94; N, 10.56. Found: C, 55.51; H, 4.21; N, 7.58.

Example 16(f):6-[N-(3-(4-tert-butyl-3-hydroxybenzamido)phenyl)-N-methylaniino]-3-E-[(3,4-methylenedioxyphenyl)ethenyl]-1H-indazole

[0266]

[0267] Example 16(f) was prepared in a similar manner to that describedfor Example 16(a), except that 3-tert-butyl-4-hydroxy-benzoic acid,HATU, and TEA were used instead of benzoyl chloride. ¹H NMR (300 MHz,CD₃OD) 8: 7.90 (d, 1H, J=8.91 Hz), 7.83 (d, 1H, J=2.29 Hz), 7.63 (dd,1H, J=8.36 Hz, J=2.31 Hz), 7.54 (t, 1H, J=1.97 Hz), 7.25-7.43 (m, 4H),7.14-7.20 (m, 2H), 7.06 (dd, 1H, J=8.11 Hz, J=1.55 Hz), 6.96 (dd, 1H,J=8.93 Hz, J=1.97 Hz), 6.90 (m, 1H), 6.82 (t, 2H, J=8.18 Hz), 6.0 (s,2H), 3.41 (s, 3H), 1.42 (s, 9H).

Example 17

[0268] Phenyl-(3-styryl-1H-indazol-6-yl)-methanone

[0269]Phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanonewas converted to phenyl-(3-styryl-1H-indazol-6-yl)-methanone asdescribed in Example 11 (30 mg, 78%). MS (ESI) [M+H]/z Calc'd 325, found325. Anal. Calc'd: C, 81.46; H, 4.97; N, 8.46. Found: C, 80.36; H, 5.16;N, 8.51.

[0270] The starting material was prepared as follows:

[0271] To a solution of6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole,prepared in Example 14, step (i), (143 mg, 0.3 mmol) in THF (1 mL)cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.2 mL,0.315 mmol) dropwise. The resulting mixture was stirred at −78° C. for30 min, then a solution of benzaldehyde (0.035 mL, 0.33 mmol) in THF(0.5 mL) was added rapidly via a cannula. After 0.5 h the reaction wasquenched with saturated NH4CI (aq) and diluted with EtOAc (10 mL) andH20 (3 mL). The phases were separated and the aqueous was extracted 2×10mL EtOAc. The pooled EtOAc was washed with brine (5 mL), dried withNa₂SO₄, decanted and concentrated under reduced pressure. The crudemixture was purified by silica gel chromatography (eluting withhexane:EtOAc 4:1) to givephenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanol(68 mg, 50% yield). R_(f) sm=0.72; R_(f) p=0.39 (7:3 hexane:EtOAc); FTIR(thin film) 3368, 2952, 2893, 1621, 1478, 1449, 1374, 1307, 1249, 1216,1078, 960, 859, 835 cm⁻¹. MS (ESI) [M+H]/z Calc'd 457, found 457.

[0272] To a solution ofphenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanol(68 mg, 0.15 mmol) in dichloromethane (3 mL) at 23° C. under anatmosphere of argon was added periodinane (Dess-Martin reagent) (190 mg,0.45 mmol). The resulting mixture was stirred at 23° C. for 1 hour. Thesolution was then diluted with hexane (3 mL) then filtered throughCelite and concentrated under reduced pressure to a solid. The crudemixture was purified by silica gel chromatography (eluting withhexane:EtOAc 9:1) to givephenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanone(54 mg, 79% yield). R_(f) sm=0.41, R_(f) p=0.63 (7:3 hexane:EtOAc); FTIR(thin film) 3059, 2952, 2894, 1659, 1474, 1448, 1307, 1249, 1078, 836,649 cm-¹. MS (ES1) [M+H]/z Calc'd 455, found 455.

Example 18: (3-Amino-phenyl)-(3-styryl-1H-indazol-6-yl)-methanone

[0273]

[0274](3-Amino-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanonewas converted to (3-amino-phenyl)-(3-styryl-1H-indazol-6-yl)-methanoneas described in Example 11. ¹H NMR (300 MHz, CDCl₃) δ 8.07 (dd, 1H,J=0.71, 8.50 Hz), 7.915(s, 1H), 7.64 (dd, 1H, J=1.35, 8.48 Hz),7.54-7.60 (m, 2H), 7.46 (d, 2H, J=12.84 Hz), 7.35-7.40 (m, 2H),7.22-7.31 (m, 2H), 7.16-7.13 (m, 2H), 6.91 (ddd, 1H, J=1.08, 7.89 Hz).LCMS (ESI) [M+H]/z Calc'd 340, found 340.

[0275] The starting material was prepared as follows:

[0276]6-Iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole wasconverted to(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanolas described in Example 17, step (i). R_(f) sm=0.71, R_(f) p=0.25 (7:3hexane:EtOAc); FIIR (thin film) 3369, 3061, 2952, 2894, 2361, 1620,1578, 1530, 1478, 1449, 1350, 1308, 1249, 1215, 1080, 961, 859 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) 8 8.35 (s, 1H), 8.14 (dd, 1H, J=1.34, 8.14 Hz),7.99 (d, 1H, J=8.38 Hz), 7.76 (d, 1H, J=7.72 Hz), 7.68 (s, 1H),7.59-7.30 (m, 8H), 7.21 (d, 1H, J=8.33 Hz), 6.09 (s, 1H), 5.73 (s, 2H),3.61 (t, 2H, J=8.30 Hz), 090 (t, 2H, J=8.30 Hz), -0.06 (s, 9H). ¹³C NMR(75 MHz, CDCl₃) 8 148.5, 145.9, 143.4, 142.4, 141.3, 137.1, 132.7,132.0, 129.5, 128.9, 128.2, 126.7, 122.6, 122.6, 121.8, 121.5, 120.8,119.6, 107.8, 77.7, 75.4, 66.8, 17.8,-1.3. Anal. Calc'd: C, 67.04; H,6.23; N, 8.38. Found: C, 66.93; H, 6.20; N, 8.41.

[0277](3-Nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanolwas converted to(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanoneas described in Example 17, step (ii) (129 mg, 91 %). R_(f) sm=0.46,R_(f) p=0.23 (7:3 hexane:EtOAc); FTIR (thin film) 3082, 2952, 2894,1665, 1613, 1532, 1476, 1349, 1298, 1250, 1080, 836,718 cm⁻¹; LCMS (ESI)[M+H]/z Calc'd. 500, found 500.

[0278](3-Nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanonewas converted to(3-amino-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanoneas described in Example 11, step (iv) (102 mg, 84%). LCMS (ESI) [M+H]/zCalc'd 340, found 340.

Example 19(a): N-[3-(3-Styryl-1H-indazole-6-carbonyl)-phenyl]-acetamide

[0279]

[0280] (3-Amino-phenyl)-(3-styryl-1H-indazol-6-yl)-methanone, preparedin Example 18, was converted toN-[3-(3-styryl-1H-indazole-6-carbonyl)-phenyl]-acetamide as described inExample 12(a) (12.2 mg, 78%). R_(f) sm=0.16, Rfp=0.35 (8:2 CH₂Cl₂:EtOAc); LCMS (ESI) [M+H]/z Calc'd 382, found 382. Anal. Calc'd: C,75.57; H, 5.02; N, 11.02. Found: C, 74.32; H, 5.41; N, 10.54.

Example 19(b): N-[3-(3-Styryl-1H-indazole-6-carbonyl)-phenyl]-benzamide

[0281]

[0282] Example 19(b) was prepared in a similar manner to that describedfor Example 19(a), except that benzoyl chloride was used instead ofacetic anhydride. ¹H NMR (300 MHz, CDCl₃) δ 8.40 (s, 1H), 8.02 (d, 1H,J=8.49 Hz), 7.98 (d, 1H, J=1.01 Hz), 7.95 (s, 1H), 7.95 (s, 1H),7.83-7.88 (m, 3H), 7.65 (dd, 1H, J=1.04, 8.48 Hz), 7.29-7.56 (m, 11H).MS (ESI) [M+H]/z Calc'd 444, found 444. Anal. Calc'd: C, 78.54; H, 4.77;N, 9.47. Found: C, 78.01; H, 4.87; N, 9.32.

Example 19(c): [3-(3-Styryl-1H-indazole-6-carbonyl)-phenyl]-carbaincacid benzyl ester

[0283]

[0284] The title compound was prepared in a similar manner to thatdescribed for Example 19(a), except that carboxybenzyloxy chloride wasused instead of acetic anhydride. ¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (d,1H, J=8.48 Hz), 7.98 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.75 (d, 2H,J=7.44 Hz), 7.61 (d, 2H, J=1.81 Hz), 7.58 (s, 1H), 7.51 (t, 1H, J=7.79Hz), 7.42 (t, 5H, J=6.56 Hz), 7.31-7.37 (m, 4H), 5.16 (s, 2H); LCMS(ESI) [M+H)/z Calc'd 474, found 474. Anal. Calc'd: C, 76.09; H, 4.90; N,8.87. Found: C, 73.82; H, 4.93; N, 8.27.

Example 19(d): 5-Methyl-thiazole-2-carboxylic acid[3-(3-styryl-1H-indazole-6-carbonyl)-phenyl]-amide

[0285]

[0286] (3-Amino-phenyl)-(3-styryl-1H-indazol-6-yl)-methanone wasconverted to 5-methyl-thiazole-2-carboxylic acid[3-(3-styryl-1H-indazole-6-carbonyl)-phenyl]-amide as described inExample 12(d) (9.9 mg, 28 %). H NMR (300 MHz, CDCl₃) δ 8.15 (d, 1H,J=8.49 Hz), 8.09 (t, 1H, J=1.86 Hz), 8.04 (dd, 1H, J=1.0, 7.98 Hz), 7.99(s, 1H), 7.75 (dd, 1H, J=1.31, 8.47 Hz), 7.67 (s, 1H), 7.63 (d, 2H,J=7.30 Hz), 7.54-7.58 (m, 3H), 7.50 (s, 1H), 7.42 (t, 3H, J=8.09 Hz);LCMS (ESI) [M+H]/z Calc'd 465, found 465.

Example 19(e):6-[3-(5-methylpyridin-3-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

[0287]

[0288] Example 19(e) was prepared in a similar manner to Example 19(d)except that 5-methyl-nicotinic acid was used instead of5-methyl-thiazole-2-carboxylic acid. ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s,1H), 8.99 (d, 1H, J=0.59 Hz), 8.67 (s, 1H), 8.24 (s, 1H), 8.16 (d, 1H,J=8.32 Hz), 2.97 (dd, 1H, J=8.3 Hz, J=0.94 Hz), 7.72 (d, 1H, J=16.65Hz), 7.64 (d, 2H, J=7.21 Hz), 7.19-7.47 (m, 8H), 6.95 (d, 1H, J=6.43Hz), 2.49 (s, 3H). MS (ESI+) [M+H]/z Calc'd 459, found 459. Anal.Calc'd: C, 75.97. H, 4.84. N, 12.22. Found: C, 75.86. H, 4.94. N, 12.10.

Example 19(f):6-[3-(indol-4-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

[0289]

[0290] Example 19 (f) was prepared in a similar manner to Example 19 (d)except 1H-Indole-4-carboxylic acid was used instead of5-methyl-thiazole-2-carboxylic acid. LCMS (ESI+) [M+H]/z Calc'd 483,found 483. Anal. Calc'd: C, 77.16; H, 4.60; N, 11.61. Found: C, 76.15;H, 4.49; N, 11.31.

Example 19(g):6-[3-(pyridin-2-ylacetamido)benzoyl]-3-E-styryl-1H-indazole

[0291]

[0292] Example 19(g) was prepared in a similar manner to Example 19(d),except that pyridin-2-yl-acetic acid was used instead. ¹H NMR (300 MHz,CDCl₃) δ 8.50 (dd, 1H, J=4.86 Hz, J=0.91 Hz), 8.37 (d, 1H, J=8.51 Hz),8.09 (s, 1H), 7.94 (d, 1H, J=7.89 Hz), 7.87 (s, 1H), 7.73-7.79 (m, 3H),7.25-7.60 (m, 10H) 3.86 (s, 2H). MS (ESI) [M+H]/z Calc'd 459, found 459.Anal. Calc'd: C, 75.97. H, 4.84. N, 12.22. Found: C, 74.70. H, 4.83. N,11.99.

Example 19(h):6-[3-(2-methylpropionaniido)benzoyl]-3-E-styryl-1H-indazole

[0293]

[0294] Example 19(h) was prepared in a similar manner to Example 19(a).Isobutyryl chloride was used instead of acetyl chloride. ¹H NMR (300MHz, DMSO-d₆) δ 8.38 (d, 1H, J=8.13 Hz), 8.08 (t, 1H), 7.96 (s, 1H,J=7.8 Hz, J=1.91 Hz), 7.88 (s, 1H), 7.75 (d, 2H, J=7.25 Hz), 7.61 (d,2H, 2.05 Hz), 7.40-7.58 (m, 5H), 7.31 (m, 1H), 2.60 (m, 1H, J=6.82 Hz),1.1 (d, 6H, J=6.82 Hz). (MS (ESI+) [M+Na]/z Calc'd 432, found 432. Anal.Calc'd: C, 76.26. H, 5.66. N, 10.26. Found: C, 75.14. H, 5.62. N, 10.08.

Example 19(i):6-[3-(2-acetamido-2-phenylacetamido)benzoyl]-3-E-styryl-1H-indazole

[0295]

[0296] Example 19(i) was prepared in a similar manner to Example 19(d)except that acetylamino-2-phenyl-acetic acid was used instead of5-methyl-thiazole-2-carboxylic acid. ¹H NMR (300 MHz, DMSO-d₆) 8 13.5(s, 1H), 10.6 (s, 1H), 8.66 (d, 1H, J=7.66 Hz), 8.36 (d, 1H, J=8.47 Hz),8.07 (s, 1H), 7.92 (d, 1H, J=7.63 Hz), 7.86 (s, 1H), 7.75 (d, 2H, J=7.33Hz), 7.29-7.60 (m, 13H), 5.61 (d, 1H, J=7.6 Hz), 1.92 (s, 3H). LCMS(ESI+) [M+H]/z Calc'd 515, found 515. Anal. Calc'd: C, 74.69. H, 5.09.N, 10.89. Found: C, 73.01. H, 5.01. N, 10.60.

Example 19(j):6-[3-(pyridin-4-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

[0297]

[0298] Example 19(j) was prepared in a similar manner to Example 19(d)except that isonicotinic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+Na]/z Calc'd 467,found 467. Anal. Calc'd: C, 75.66; H, 4.54; N, 12.60. Found: C, 74.17;H, 4.62; N, 12.31.

Example 19(k):6-[3-(pyridin-2-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

[0299]

[0300] Example 19(k) was prepared in a similar manner to Example 19(d)except that pyridine-2-carboxylic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+Na]/z Calc'd 467,found 467. Anal. Calc'd: C, 75.66; H, 4.54; N, 12.60. Found: C, 74.17;H, 4.61; N, 12.44.

Example 19(l):6-[3-(isoxazol-4-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

[0301]

[0302] Example 19(1) was prepared in a similar manner to Example 19(d)except that isoxazole-5-carboxylic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+H]/z Calc'd 435, found435. Anal. Calc'd: C, 71.88; H, 4.18; N, 12.90. Found: C, 71.36; H,4.33; N, 12.47.

Example 19(m):6-[3-(6-chloropyridin-2-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

[0303]

[0304] Example 19(m) was prepared in a similar manner to Example 19(d)except that 6-chloro-pyridine-2-carboxylic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+Na]/z Calc'd 501,found 501.

Example 19(n):6-[3-(4-chloropyridin-2-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

[0305]

[0306] Example 19(n) was prepared in a similar manner to Example 19(d)except 4-chloro-pyridine-2-carboxylic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+H]/z Calc'd 479, found479. Anal. Calc'd: C, 70.22; H, 4.00; N, 11.70. Found: C, 70.07; H,4.09; N, 11.64.

Example 19(o):6-[3-(2-chloropyridin-4-ylcarboxamodo)benzoyl]-3-E-styryl-1H-indazole

[0307]

[0308] Example 19(o) was prepared in a similar manner to Example 19(d)except 2-chloro-isonicotinic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+H]/z Calc'd 479, found479.

Example 19(p):6-[3-(2-methylamino-2-phenylacetamido)benzoyl]-3-E-styryl-1H-indazole

[0309]

[0310] To a solution of6-[3-(2-(N-t-butoxycarbonyl-N-methylamino)-2-phenyl-acetamido)benzoyl]-3-E-styryl-1H-indazole(115 mg, 0.2 mmol) in CH₂Cl₂ (2 ml) cooled to 0° C. was added TFA (2ml). After 40 min. the reaction mixture was quenched with saturatedNaHCO₃ (aq), then extracted with CH₂Cl₂ (2×10 ml). The Organics werewashed with brine, dried with Na₂SO₄, decanted and concentrated.Purification by silica gel chromatography (1:10methanol-dichloromethane) gave6-[3-(2-methylamino-2-phenylacetamido)benzoyl]-3-E-styryl-1H-indazole(38 mg, 39%). MS (ESI+) [M+H]/z Calc'd 487, found 487. Anal. Calc'd: C,76.52; H, 5.39; N, 11.51. Found: C, 74.99; H, 5.76; N, 10.89.

[0311] The starting material was prepared as described below:

[0312] (i)6-[3-(2-(N-t-butoxycarbonyl-N-methylamino)-2-phenyl-acetamido)benzoyl]-3-E-styryl-1H-indazole

[0313]6-[3-(2-(N-t-butoxycarbonyl-N-methylamino)-2-phenyl-acetamido)benzoyl]-3-E-styryl-1H-indazolewas prepared in a similar manner to Example 19(d) except that(t-butoxycarbonyl-methyl-amino)-phenyl-acetic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+H]/z Calc'd 587, found587.

Example 20(a): 6-(3-Acetanido-phenylsulfanyl)-3-styryl-1H-indazole

[0314]

[0315]6-(3-Acetamido-phenylsulfanyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas converted to 6-(3-acetamido-phenylsulfanyl)-3-styryl-1H-indazole asdescribed in Example 11 (30 mg, 81%): R_(f) sm 0.65, p 0.35 (10%methanol in dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, 1H,J=8.5 Hz), 7.59 (bs, 1H), 7.48-7.0 (m, 13H), 1.98 (s, 3H); HRMS (FAB)[M+Na]/z Calc'd 408.1147, found 408.1156.

[0316] The starting material was prepared as follows:

[0317] To the 9-BBN adduct of 3-phthalamido-thiophenol (1.4 equiv),which was prepared in situ as described below, was added3,6-Diiodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (250 mg,0.5 mmol), Pd(dppf)Cl₂ (87 mg, 0.2 equiv) and potassium phosphate (339mg, 1.6 mmol, 3.00 equiv) in DMF (3.0 mL). The reaction mixture washeated to 90° C. for 9 h. The mixture was cooled and partitioned betweenethyl acetate and saturated sodium bicarbonate. The organic material wasdried over sodium sulfate, decanted and concentrated. Purification bysilica gel chromatography (2:8 ethyl acetate-hexane) gave6-(3-phthalamido-phenylsulfanyl)-3-iodo-1H-indazole as an oil (159 mg,50%): ¹H NMR (300 MHz, CDCl₃) 8 7.93 (m, 2H), 7.79 (m, 2H), 7.62 (s,1H), 7.5-7.3 (m, 5H), 7.22 (d, 1H), 5.68 (s, 2H), 3.55 (t, 2H, J=8.2Hz), 0.87 (t, 2H, J=8.2 Hz), −0.06 (s, 9H); HRMS (FAB) [M+Cs]/z Calc'd759.9563, found 759.9571.

[0318] The boron reagent was prepared as follows: In a 10 mL Schlenkflask 3-phthalamido-thiophenol was dried under high vacuum. To this wasadded a solution of 9-BBN (0.5 M in THF, 1.6 mL, 1.0 equiv). The mixturewas heated to 55° C. for 2 h. The volatile material was removed under astream of argon at 70° C. for 1.5 h. The residue was used withoutfurther manipulation.

[0319] 6-(3-Phthalamido-phenylsulfanyl)-3-iodo-1H-indazole was convertedto 6-(3-phthalamido-phenylsulfanyl)-3-styryl-1H-indazole as described inExample 11, step (iii). 1H NMR (300 MHz, CDCl₃) δ 7.93 (m, 3H), 7.78 (m2H), 7.7 (s, 1H), 7.58 (m, 2H), 7.47-7.26 (m, 10H), 5.71 (s, 2H), 3.59(t, 2H, J=8.2 Hz), 0.89 (t, 2H, J=8.2 Hz), −0.06 (s, 9H); HRMS (FAB)[M+Cs]/z Calc'd 736.1066, found 736.1058.

[0320] To a solution of6-(3-phthalamidophenylsulfanyl)-3-styryl-1H-indazole (121 mg, 0.2 mmol)in ethanol (3.5 mL) was added hydrazine (63 μL, 2.0 mmol, 10 equiv). Thereaction mixture was allowed to stir at 23° C. for 45 min and wasdiluted with saturated sodium bicarbonate and ethyl acetate. The organicmaterial was dried over sodium sulfate, decanted and concentrated.Purification by silica gel chromatography (3:7 ethyl acetate-hexane)gave 6-(3-aminophenylsulfanyl)-3-styryl-1H-indazole as an oil (79 mg,90%): ¹H NMR (300 MHz, CDCl₃) 6 7.92 (d, 1H, J=8.5 Hz), 7.57 (m, 3H),7.49 (d, 1H, J=16.8 Hz), 7.4-7.25 (m, 4H), 7.23 (dd, 1H, J=1.5, 8.5 Hz),7.11 (t, 1H, J=7.9 Hz), 6.79 (m, 1H), 6.70 (t, 1H, J=1.9 Hz), 6.59 (m,1H), 5.66 (s, 2H), 3.60 (bs, 2H), 3.59 (t, 2H, J=8.2 Hz), 0.90 (t, 2H,J=8.2 Hz), −0.05 (s, 9H); HRMS (FAB) [M+H]/z Calc'd 474.2035, found474.2019.

[0321] To a solution of 6-(3-aminophenylsulfanyl)-3-styryl-1H-indazole(43.7 mg, 0.10 mmol) in dichloromethane (0.5 mL) was added pyridine (81μL, 1.0 mmol, 10 equiv), and acetic anhydride (47 μL, 0.5 mmol, 5equiv). The mixture was allowed to stir for 10 min at 23° C. . Themixture was diluted with water and the product was extracted with 30%hexane in ethyl acetate. The organic material was washed with 5% citricacid and saturated sodium bicarbonate. The organic material was driedover sodium sulfate, decanted and concentrated. Purification by silicagel chromatography (3:7 ethyl acetate-hexane) gave6-(3-acetamido-phenylsulfanyl)-3-styryl-1H-indazole as an oil (50 mg,97%): R_(f) sm 0.33, Rfp 0.18 (ethyl acetate-hexane 3:7); ¹H NMR (300MHz, CDCl₃) δ 7.94 (d, 1H), 7.65-7.1 (m, 13H), 5.70 (s, 2H), 3.62 (t,2H, J=8.2 Hz), 2.18 (s, 3H), 0.93 (t, 2H, J=8.2 Hz), -0.05 (s, 9H). HRMS(FAB) [M+Cs]/z Calc'd 648.1117, found 648.1098.

Example 20(b): 6-(3-(Benzoylaniido)-phenylsulfanyl)-3-styryl-1H-indazole

[0322]

[0323] The title compound was prepared like Example 20(a),, except thatbenzoyl chloride was used instead of acetic anhydride in step (iv). ¹HNMR (300 MHz, CDCl₃) δ 8.03 (s, 1H), 7.73 (d, 1H, J=8.5 Hz), 7.63 (m,2H). 7.47 (m, 1H), 7.42 (t, 1H, J=1.9 Hz), 7.37 (m, 3H), 7.31 (m, 1H),7.28-6.98 (m, 9H); HRMS (FAB) [M+H]/z Calc'd 448.1484, found 448.1490.

Example 21: 6-(1-(3-Aminophenyl)-vinyl)-3-styryl-1H-indazole

[0324]

[0325]6-(1-(3-Aminophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas converted to the title compound as described for Example 11 (85 mg,85%): R_(f) sm 0.72, p 0.37 (ethyl acetate-hexane 1:1); FlIR (thin film)3385, 3169, 2953, 1621, 1581, 1489, 1447, 1349, 1251, 1165, 1071, 959,906, 870, 817 cm-¹; 1H NMR (300 MHz, CDCl₃) δ 7.98 (d, 1H, J=8.5 Hz),7.60 (m, 2H), 7.51 (s, 1H), 7.48 (s, 1H), 7.40 (m, 3H), 7.29 (m, 2H),7.15 (m, 1H), 6.78 (m, 1H), 6.68 (m, 2H), 5.50 (s, 2H), 3.65 (bs, 2H);MS (ES) [M+H]/z Calc'd 338, found 338; MS (ES) [M-H]/z Calc'd 336, found336.

[0326] The starting material was prepared as follows:

[0327] To a solution of6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole,prepared in Example 14, step (i), (330 mg, 0.693 mmol) in THF (3.0 mL)at −78° C. was added n-butyllithium (0.56 mL, 1.5 M, 1.2 equiv). After20 min, this solution was then added to anhydrous zinc chloride (170 mg)and the mixture was warmed to 23° C. and stirred for 15 min. To thismixture was added 1-(3-nitro-phenyl)vinyltriflate (146 μL, 1.05 equiv)and Pd(PPh₃)₄ (40 mg, 0.05 equiv). This mixture was stirred for 30 min,was partitioned between ethyl acetate and saturated sodium bicarbonateand the organic layer was separated. The organic material was dried oversodium sulfate, decanted and concentrated under reduced pressure.Purification by silica gel chromatography (1:9 ethyl acetate-hexane)then a second column (1% ethyl acetate/benzene) gave6-(1-(3-nitrophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazoleas an oil (180 mg, 52%): FTIR (thin film) 2951, 1616, 1530, 1477, 1448,1348, 1305, 1248, 1217, 1077, 961, 913, 859 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) δ 8.26 (t, 1H, J=1.9 Hz), 8.21 (m, 1H), 8.00 (d, 1H, J=8.5 Hz),7.69 (dt, 1H, J=1.4, 7.8), 7.62-7.28 (m, 9H), 7.19 (dd, 1H, J=1.4, 8.4Hz), 5.72 (s, 3H), 5.69 (s, 1H), 3.60 (t, 2H, J=8.2 Hz), 0.89 (t, 2H,J=8.2 Hz), -0.05 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 149.9, 149.6, 144.7,144.5, 142.8, 140.7, 138.6, 135.6, 133.1, 130.7, 130.2, 129.4, 128.0,124.4, 124.2, 124.1, 123.8, 122.6, 121.2, 118.9,111.0,79.2,68.0, 19.2,0.0; HRMS (FAB) [M+Na]/z Calc'd 520.2031, found 520.2046.

[0328]6-(1-(3-Nitrophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas converted to6-(1-(3-aminophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazoleas described in Example 11, step (iv) (140 mg, 95%): R_(f) sm 0.59, p0.46 (ethyl acetate-hexane 4:6); FTIR (thin film) 3460, 3366, 3223,3084, 3028, 2952, 2894, 2246, 1616, 1601, 1581, 1489, 1474, 1448, 1359,1303, 1249, 1217, 1076, 961, 909, 860, 836, 733, 692 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ 7.96 (d, 1H, J=8.5 Hz), 7.59 (m, 3H), 7.50 (s, 1H), 7.46(s, 1H), 7.40 (m, 2H), 7.30 (m, 1H), 7.25 (m, 1H), 7.14 (m, 1H), 6.77(m, 1H), 6.68 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) 8 151.6, 147.7, 144.6,143.9, 142.8, 142.4, 138.6, 132.8, 130.6, 130.2, 129.3, 128.0,124.4,123.6, 121.9, 121.5, 120.2, 116.4, 116.1, 110.8, 79.0, 67.9, 19.2, 0.0;HRMS (FAB) [M+Na]/z Calc'd 490.2291, found 490.2302.

Example 22(a):6-(1-(3-(5-Methyl-thiaxole-2-carboxoylamido)phenyl)-vinyl)-3-styryl-1H-indazole

[0329]

[0330] 6-(1-(3-Aminophenyl)-vinyl)-3-styryl-1H-indazole was converted tothe title compound as described in Example 12(d) (20 mg, 72%): FrIR(thin film) 3271, 1673, 1605, 1585, 1538, 1486, 1428, 1349, 1304, 1090,960, 907, 871 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 10.7 (bs, 1H), 9.09 (s,1H), 8.0 (d, 1H), 7.79 (m, 1H), 7.60 (m, 3H), 7.51 (m, 3H), 7.44-7.15(m, 7H), 5.59 (s, 2H), 2.54 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 162.2,157.9, 149.8, 144.4, 142.8, 142.2, 141.9, 141.5, 140.6, 137.63, 137.56,131.6, 129.5, 129.1, 128.3, 126.9, 125.1, 122.6, 121.2, 120.9, 120.5,120.2, 119.8, 116.1, 110.2, 12.8; HRMS (FAB) [M+H]/z Calc'd 463.1593,found 463,1582.

Example 22(b): 6-(1-(3-(Benzoylamido)phenyl)-vinyl)-3-styryl-1H-indazole

[0331]

[0332] Example 22(b) was prepared in a similar manner to that describedfor Example 22(a), except that benzoyl chloride was used instead of5-methyl-thiazole-2-carboxylic acid and HATU. FTIR (thin film) 3243,1651, 1606, 1580, 1538, 1485, 1447, 1428, 1349, 1307, 1258, 1073, 959,907 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 9.09 (s, 1H), 7.99 (d, 1H, J=8.5Hz), 7.78 (m, 1H), 7.60 (m, 3H), 7.51 (m, 3H), 7.43-7.15 (m, 10H), 5.56(d, 2H, J=3.2 Hz); 13C NMR (75 MHz, CDCl₃) δ 166.5, 149.7, 144.3, 142.7,142.1, 140.6, 138.1, 137.6, 135.0, 132.3, 131.6, 129.4, 129.1, 128.3,127.4, 126.9, 125.0, 122.5, 120.9, 120.8, 120.6, 120.5, 115.9, 110.2;HRMS (FAB) [M+H]/z Calc'd 442.1919, found 442.1919.

Example 22(c): 6-(1-(3-(Benzoylamido)phenyl)-vinyl)-3-styryl-1H-indazole

[0333]

[0334] The title compound was prepared in a similar manner to thatdescribed for Example 22(a), except that carbobenzyloxy chloride wasused instead of 5-methyl-thiazole-2-carboxylic acid and HATU. FTIR (thinfilm) 3305, 1712, 1606, 1586, 1537, 1487, 1445, 1348, 1216, 1059, 959,908 cm-¹; ¹H NMR (300 MHz, CDCl₃) δ 7.99 (d, 1H, J=8.5 Hz), 7.6-7.0 (m,18H), 5.55 (s, 2H), 5.19 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 153.9,149.8, 144.3, 142.7, 142.1, 140.7, 138.2, 137.6, 136.3, 131.7, 129.4,129.1, 129.0, 128.7, 128.7, 128.3, 126.9, 124.0, 122.6, 121.1, 120.8,120.4, 115.9, 110.1, 67.4; HRMS (FAB) [M+H]/z Calc'd 472.025, found472.2026.

Example 23: 6-(1-(3-Acetamido-phenyl)-vinyl)-3-styryl-1H-indazole

[0335]

[0336]6-(1-(3-Acetamido-phenyl)-vinyl)-3-styryl-1-[2-trimethylsilanyl-ethoxymethyl]-1H-indazolewas converted to 6-(1-(3-acetamido-phenyl)-vinyl)-3-styryl-1H-indazoleas described for Example 11: FTIR (thin film) 3252, 1667, 1606, 1557,1486 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 10.4 (bs, 1H), 7.91 (d, 1H, J=8.5Hz), 7.5-7.0 (m, 13H), 5.47 (s, 2H), 2.10 (s, 3H); MS (ES) [M+H]/zCalc'd 380, found 380; [M-H]/z Calc'd 378, found 378.

[0337] The starting material was prepared as follows:

[0338]6-(1-(3-Aminophenyl)-vinyl)-3-styryl-1-[2-trimethylsilanyl-ethoxymethyl]-1H-indazolewas converted to6-(1-(3-acetamido-phenyl)-vinyl)-3-styryl-1-[2-trimethylsilanyl-ethoxymethyl]-1H-indazoleas described for Example 12(a): R_(f) sm 0.42, p 0.26 (ethylacetate-hexane 4:6); FTIR (thin film) 3305, 3059, 2952, 1667, 1608,1585, 1555, 1486, 1448, 1433, 1369, 1306, 1249, 1076, 912, 859, 836,748, 693 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, 1H, J=8.5 Hz), 7.7-7.4(m, 9H), 7.35 (m, 2H), 7.26 (dd, 1H, J=1.3, 8.4 Hz), 7.16 (bd, 1H, J=7.8Hz), 5.75 (s, 2H), 5.62 (s, 1H), 5.61 (s, 1H), 3.66 (t, 2H, J=8.2 Hz),2.16 (s, 3H), 0.98 (t, 2H, J=8.2 Hz), −0.02 (s, 9H); ¹³C NMR (75 MHz,CDCl₃) δ 169.8, 150.9, 144.6, 143.5, 142.8, 142.0, 139.4, 138.6, 132.9,130.3, 129.3, 127.9, 125.6, 124.2, 123.7, 122.0, 121.3, 121.0, 117.1,110.8, 68.0, 25.8, 19.1, 0.0; HRMS (FAB) [M+Na]/z Calc'd 532.2396, found532.2410.

Example 24(a):4-[3-(1-H-Benzoimidazol-2-yl)-1-H-indazol-6-yl]-2-methoxy-5-methyl-phenol

[0339]

[0340]6-{15-Methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl}-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzamidazol-2-yl}-1-H-indazole(326 mg, 0.43 mmol) was stirred in a solution of TBAF (4.5 mL of 1 M inTHF, which was concentrated in vacuo to 2.5 mL) and ethylenediamine (0.6mL, 8.9 mmol) at reflux for 40 h. The reaction was diluted with ethylacetate/THF (40 mL/5 mL) and washed with H₂O (20 mL) and brine (20 mL).Organics were dried (MgSO₄) and concentrated in vacuo. Purification bysilica gel chromatography (60% THF/hexanes) and then precipitation fromchloroform gave 108 mg (68%) of4-[3-(1-H-benzoimidazol-2-yl)-1-H-indazol-6-yl]-2-methoxy-5-methyl-phenolas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.62 (s, 1 H), 13.05 (brs, 1 H), 9.01 (s, 1 H), 8.50 (d, 1 H, J=8.4 Hz), 7.62 (br s, 2 H), 7.49(s, 1 H), 7.28-7.20 (m, 3 H), 6.85 (s, 1H), 6.74 (s, 1 H), 3.77 (s, 3H), 2.15 (s, 3 H). Anal. (C₂₂H₁₈N₄O_(2.)1.3 H₂O) C, H, N. Calculated: C,67.10; H, 5.27; N, 14.23. Found: C, 67.30; H, 5.27; N, 14.11.

[0341] The starting materials were prepared as follows:

[0342] Preparation of2-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole. Asolution of 1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole(5.029 g, 20.25 mmol) (see Witten et al., J. Org. Chem., 51, 1891-1894(1986)) in THF (50 mL) was cooled to −78° C. and added dropwise over 12min via cannula to a flask containing n-butyllithium (2.5 M in hexanes,12.2 mL) in THF (30 mL) at −78° C. under argon. After stirring for 25min at −78° C., the flask was warmed to 0° C. for 10 min, then cooledagain to −78° C. This solution was then added via cannula to a secondflask containing iodine (25.7 g, 101 mmol) in THF (50 mL) at −78° C.Once the addition was complete (˜5 min), the cooling bath was removed,and stirring was continued for 30 min. The reaction mixture waspartitioned between ethyl acetate (500 mL) and water (100 mL). Theorganic layer was washed with saturated aqueous sodium metabisulfite(2×100 mL) to remove the dark iodine color, dried (MgSO₄), andconcentrated in vacuo. Purification by flash chromatography (10% to 50%ethyl acetate/hexanes) yielded 4.79 g (63%) of pure2-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole as ayellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.76-7.72 (m, 1 H), 7.54-7.51(m, 1 H), 7.29-7.25 (m, 2 H), 5.54 (s, 2 H), 3.59 (t, 2 H, J=8.1 Hz),0.92 (t, 2 H, J=8.1 Hz), -0.03 (s, 9 H). Anal. (Cl₃Hl₉IN₂0S) C, H.Calculated: C, 41.71; H, 5.12; L 33.90; N, 7.48. Found: C, 41.90; H,5.09; I, 34.00; N, 7.37.

[0343] Preparation of6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazole:3-Iodo-6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-indazole (10.0g, 23.9 mmol) and hexamethylditin (10.0 g, 30.5 mmol) were combined withdry toluene (45 mL) in a flask purged with argon.Tetrakis(triphenylphosphine)-palladium(0) (300 mg, 0.26 mmol) was added,and the reaction stirred at reflux under argon for 2.5 h. The reactionwas cooled to 23° C. and diluted with ether (60 mL). Organics werewashed with 0.1N HCl (20 mL) and brine (20 mL), dried (MgSO₄), andconcentrated. Purification by silica gel chromatography (3% to 8%ether/hexanes) gave 7.70 g (71%) of6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazoleas a faintly yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, 1 H, J=1.8Hz), 8.03 (dd, 1 H, J=8.7, 1.8 Hz), 7.81 (d, 1 H, J=8.7 Hz), 5.84 (s, 2H), 3.58 (t, 2 H, J=8.1 Hz), 0.90 (t, 2 H, J=8.1 Hz), 0.50 (t, 9 H,J=28.2 Hz), −0.05 (s, 9 H). Anal. (Cl6H₂₇N₃0₃SiSn) C, H, N. Calculated:C, 42.13; H, 5.97; N, 9.21. Found: C, 42.39; H, 6.01; N, 9.26.

[0344] Preparation of6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole:6-Nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazole(7.50 g, 16.4 mmol),3-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzimidazole (6.50 g,17.4 mmol), and copper(I) iodide (313 mg, 1.64 mmol) were combined withdry THF (150 mL) in a flask purged with argon.Tetrakis(triphenylphosphine)palladium(0) was added, and the reactionstirred at reflux under argon for 23 h. The reaction was cooled andadsorbed directly onto silica gel (˜16 g). Purification by silica gelchromatography (4% to 15% ethyl acetate/hexanes) gave 7.28 g (82%) of6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazoleas a light yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.91 (d, 1 H, J=9.0Hz), 8.59 (d, 1 H, J=1.8 Hz), 8.22 (dd, 1 H, J=8.7, 1.8 Hz), 7.92-7.89(m, 1 H), 7.66-7.62 (m, 1 H), 7.40-7.36 (m, 2 H), 6.24 (s, 2 H), 5.90(s, 2 H), 3.68-3.59 (m, 4 H), 0.94 (t, 2 H, J=8.1 Hz), 0.86 (t, 2 H,J=8.1 Hz), -0.04 (s, 9 H), −0.15 (s, 9 H). Anal. (C₂₆H₃₇N₅O₄Si₂) C, H,N. Calculated: C, 57.85; H, 6.91; N, 12.97. Found: C, 57.60; H, 6.81; N,12.82.

[0345] Preparation of6-Amino-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole:Tin(lI) chloride (12.0 g, 63.3 mmol) was added to a solution of6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole(7.18 g, 13.3 mmol) in DMF/1H₂O (160 mL/10 mL), and the reaction stirredat 50° C. for 2.5 h. The reaction was cooled to 0° C., and saturatedsodium bicarbonate was added slowly, with mixing, until all frothingfrom quenching had subsided. The material was concentrated in vacuo andtaken up in ether (100 mL). Insoluble material was removed by filtrationand rinsed with ether (50 mL). The filtrate was washed with brine (50mL), dried (Na₂SO₄), and concentrated in vacuo. Purification by silicagel chromatography (25% ethyl acetate/hexane) gave 6.05 g (89%) of6-amino-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazoleas a faintly yellow waxy solid. ¹H NMR (300 MHz, CDCl₃) δ 8.40 (d, 1 H,J=9.0 Hz), 7.89-7.86 (m, 1 H), 7.63-7.60 (m, 1 H), 7.35-7.31 (m, 2 H),6.78 (dd, 1 H, J=8.7, 1.8 Hz), 6.75 (s, 1 H), 6.25 (s, 2 H), 5.69 (s, 2H), 3.93 (br s, 2 H), 3.65-3.55 (m, 4 H), 0.93 (t, 2 H, J=8.1 Hz), 0.85(t, 2 H, J=8.1 Hz), −0.04 (s, 9 H), −0.15 (s, 9 H). Anal.(C₂₆H₃₉N₅0₂Si₂) C, H, N. Calculated: C, 61.26; H,7.71; N, 13.74. Found:C, 61.18; H, 7.65; N, 13.82.

[0346] Preparation of6-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole:A solution of6-amino-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole(500 mg, 0.98 mmol) in acetic acid (1.5 mL) was diluted with H₂0 (1.0mL) and stirred at 0° C. Concentrated HCl (250 μL, ˜3 mmol) in H₂0 (250μL) was added. Sodium nitrate (90 mg, 1.3 mmol) in H₂O (300 μL) wasadded, and the reaction stirred for 8 min. Iodine (10 mg) and a solutionof potassium iodide (250 mg, 1.3 mmol) in H₂O (250 μL) were added, andthe frothing reaction stirred for 30 min at 23° C. The reaction wasdiluted with H₂O (25 mL) and extracted with ethyl acetate (2×20 mL).Organics were washed with saturated sodium metabisulfite solution (10mL) and brine (10 mL), dried (Na₂SO₄), and concentrated in vacuo.Purification by silica gel chromatography (8% ethyl acetate/hexanes)gave 316 mg (52%) of6-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazoleas a faintly yellow oil, which slowly crystallized to a white solid. ¹HNMR (300 MHz, CDCl₃) δ 8.45 (d, 1 H, J=9.0 Hz), 8.05 (s, 1 H), 7.91-7.88(m, 1 H), 7.67-7.62 (m, 2 H), 7.38-7.34 (m, 2 H), 6.24 (s, 2 H), 5.77(s, 2 H), 3.65-3.57 (m, 4 H), 0.93 (t, 2 H, J=8.1 Hz), 0.85 (t, 2 H,J=8.1 Hz), −0.04 (s, 9 H), -0.15 (s, 9 H). Anal. (C₂₆H₃₇IN₄0₂Si₂) C, H,N. Calculated: C, 50.31; H, 6.01; N, 9.03. Found: C, 50.55; H, 6.08; N,9.00.

[0347] Preparation of[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane:4-Bromo-2-methoxy-5-methyl-phenol (see Chien-Hsun et al., Syn. Lett.,12, 1351-1352 (1997)) was stirred in dry CH₂CI₂ (100 ML) at 23° C. DIEA(6.05 mL, 34.6 mmol), and then 2-(trimethylsilyl)ethoxymethyl chloride(5.6 mL, 31.7 mmol) were added. After stirring for 1 h, the solution waswashed with H₂O, 0.1 N HCl, H₂O, saturated NaHCO₃, and brine (25 mLeach). Organics were dried (Na₂SO₄) and concentrated in vacuo.Purification by silica gel chromatography (6% ethyl acetate/hexanes)gave 9.06 g (91%) of[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silaneas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.06 (s, 1 H), 7.02 (s, 1 H),5.24 (s, 2 H), 3.84 (s, 3 H), 3.79 (t, 2 H, J=8.4 Hz), 2.31 (s, 3 H),0.96 (t, 2 H, J=8.4 Hz), 0.01 (s, 9 H).

[0348] Preparation of5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid:[2-(4-Bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane(2.6 g, 7.5 mmol) was stirred in dry THF (10 mL) at −78° C. under argon.n-Butyllithium (3.75 mL, 2.5 M in hexanes, 9.36 mmol) was addeddropwise, and the reaction stirred for 30 min before it was transferredvia cannula to a flask of trimethyl borate (8.4 mL, 75 mmol) in THF (15mL), which was also stirring at −78° C. under argon. After addition wascomplete, the reaction stirred 30 min at −78° C. and then 30 min whilewarming to 0° C. It was then quenched with H₂O (20 mL), acidified with0.1 N HCl, and extracted with ethyl acetate (2×25 mL). Organics werewashed with brine (20 mL), dried (Na₂SO₄), and concentrated in vacuo.Purification by silica gel chromatography (20% to 50% ethylacetate/hexanes) gave 1.11 g (47%) of5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.78 (s, 1 H), 7.10 (s,1 H), 5.36 (s, 2 H), 3.93 (s, 3 H), 3.83 (t, 2 H, J=8.4 Hz), 2.79 (s, 3H), 0.98 (t, 2 H, J=8.4 Hz), 0.01 (s, 9 H). Anal. (Cl₄H₂₅BO₅Si—H₂O) C,H. Calculated: C, 57.15; H, 7.88. Found: C, 56.89; H, 7.87.

[0349] Preparation of6-{5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl}-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzamidazol-2-yl}-1-H-indazole.6-Iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole(350 mg, 0.56 mmol),5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid (211 mg, 0.68 mmol), and sodium carbonate (72 mg, 0.68 mmol) werestirred in a mixture of benzene (5 mL), H₂O (330 pL), and methanol (1mL) in a flask purged with argon.Tetrakis(triphenylphosphine)palladium(0) was added, and the reactionstirred at reflux under argon for 16 h. After cooling to 23° C., thereaction was diluted with ether (20 mL), washed with H₂O (10 mL) andbrine (10 mL), dried (Na₂SO₄), and concentrated in vacuo. Purificationby silica gel chromatography (15% ethyl acetate/hexanes) gave 382 mg(89%) of6-{5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl}-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzamidazol-2-yl}-1-H-indazoleas a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, 1 H, J=8.4 Hz),7.93-7.90 (m, 1 H), 7.67-7.63 (m, 1 H), 7.54 (s, 1 H), 7.38-7.32 (m, 3H), 7.13 (s, 1 H), 6.86 (s, 1 H), 6.29 (s, 2 H), 5.83 (s, 2 H), 5.34 (s,2 H), 3.89 (s, 3 H), 3.86 (t, 2 H, J=8.4 Hz), 3.69-3.58 (m, 4 H), 2.22(s, 3 H), 1.01 (t, 2 H, J=8.4 Hz), 0.95-0.83 (m, 4 H), 0.03 (s, 9 H),−0.05 (s, 9 H), −0.15 (s, 9 H). Anal. (C₄₀H₆₀N₄O₅Si₃) C, H, N.Calculated: C, 63.12; H, 7.95; N, 7.36. Found: C, 63.22; H, 7.93; N,7.46.

Example 24(b):4-[3-(1-H-Benzoimidazol-2-yl)-1-H-indazol-6-yl]-3-methyl-phenol

[0350]

[0351] To prepare the title compound, the procedure described forExample 24(a) was followed, with2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid(prepared as described below) substituted for5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid in step (viii). ¹H NMR (300 MHz, DMSO-d₆) δ 13.60 (s, 1 H), 12.99(br s, 1 H), 9.41 (s, 1 H), 8.49 (d, 1 H, J=8.4 Hz), 7.72 (br s, 1H),7.52 (br s, 1 H), 7.45 (s, 1 H), 7.25-7.21 (m, 3 H), 7.12 (d, 1 H, J=8.1Hz), 6.73-6.67 (m, 2 H), 2.20 (s, 3 H). Anal. (C₂₁H₁₆N₄O 0.7 H₂O) C, H,N. Calculated: C, 71.45; H, 4.97; N, 15.87. Found: C, 71.44; H, 4.96; N,15.77.

[0352] 2-Methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid was prepared as follows:

[0353] [2-(4-Bromo-3-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane wasprepared in 86% yield from 4-bromo-3-methyl-phenol according to theprocedure for[²-(⁴-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane.¹H NMR (300 MHz, CDCl₃) δ 7.39 (d, 1 H, J=8.7 Hz), 6.93 (d, 1 H, J=2.7Hz), 6.75 (dd, 1 H, J=8.7, 2.7 Hz), 5.16 (s, 2 H), 3.74 (t, 2 H, J=8.4Hz), 2.36 (s, 3 H), 0.95 (t, 2 H, J=8.4 Hz), 0.01 (s, 9 H). Anal.(Cl₃H₂₁BrO₂Si) C, H. Calculated: C, 49.21; H, 6.67. Found: C, 49.33; H,6.67.

[0354] 2-Methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid was prepared in 52% yield from[2-(4-bromo-3-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane accordingto the procedure for5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid above. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, 1 H, J=8.1 Hz), 6.98-6.92(m, 2 H), 5.29 (s, 2 H), 3.78 (t, 2 H, J=8.4 Hz), 2.78 (s, 3 H), 0.98(t, 2 H, J=8.4 Hz), 0.01 (s, 9 H). Anal. (Cl₃H₂₃BO₄Si—H₂O) C, H.Calculated: C, 59.10; H, 8.01. Found: C, 59.07; H, 8.08.

Example 24(c):4-[3-(1-H-Benzoimidazol-2-yl)-1-H-indazol-6-yl]-2-chloro-5-methyl-phenol

[0355]

[0356] To prepare the title compound,5-chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid, prepared as described below, was substituted for5-methoxy-²-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid in the procedure described in Example 24(a), step (viii). ¹H NMR(300 MHz, DMSO-d₆) δ 13.61 (s, 1 H), 13.00 (br s, 1 H), 10.22 (s, 1 H),8.51 (d, 1 H, J=8.4 Hz), 7.64 (br s, 2 H), 7.50 (s, 1 H), 7.26-7.21 (m,4 H), 6.95 (s, 1 H), 2.19 (s, 3 H).

[0357]5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid was prepared as follows:

[0358] 2-Chloro-5-methyl-phenol (6.68 g, 46.9 mmol) was stirred inacetonitrile (200 mL). N-Bromosuccinimide (8.5 g, 47.8 mmol) was added,and the reaction stirred for 45 min. The solution was concentrated invacuo and re-dissolved in chloroform (100 mL). Organics were washed withsaturated NaHCO₃ (50 mL) and brine (50 mL), dried (MgSO₄), andconcentrated in vacuo. Purification by silica gel chromatography (8%ethyl acetate/hexanes) gave 7.98 g (77%) of4-bromo-3-chloro-5-methyl-phenol as a clear oil. ¹H NMR (300 MHz, CDCl₃)8 7.47 (s, 1 H), 6.91 (s, 1 H), 5.52 (br s, 1 H), 2.32 (s, 3 H). Anal.(C₇H₆ClBrO.0.1 H₂O) C, H. Calculated: C, 37.66; H, 2.80. Found: C,37.57; H, 2.82.

[0359][2-(4-Bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silanewas prepared in 83% yield from 4-bromo-3-chloro-5-methyl-phenolaccording to the procedure for[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane.¹H NMR (300 MHz, CDCl₃) δ 7.51 (s, 1 H), 7.09 (s, 1 H), 5.26 (s, 2 H),3.79 (t, 2 H, J=8.4 Hz), 2.35 (s, 3 H), 0.95 (t, 2 H, J=8.4 Hz), 0.02(s, 9 H). Anal. (Cl₃H₂₀ClBrO₂Si) C, H. Calculated: C, 44.39; H, 5.73.Found: C, 45.08; H, 5.91.

[0360]5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid was prepared in 54% yield from[2-(4-bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silaneaccording to the procedure for5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid. ¹H NMR (300 MHz, CDCl₃) δ 8.11 (s, 1 H), 7.09 (s, 1 H), 5.37 (s, 2H), 3.84 (t, 2 H, J=8.4 Hz), 2.76 (s, 3 H), 0.98 (t, 2 H, J=8.4 Hz),0.01 (s, 9 H). Anal. (Cl₃H₂₂BClO₄Si—H₂O) C, H, Calculated: C, 52.28; H,6.75. Found: C, 51.98; H, 6.84.

Example 24(d):3-1H-Benzoimidazol-2-yI-6-(4-hydroxy-2-methoxyphenyl)-1H-indazole

[0361]

[0362] Example 24 (d) was prepared in a similar manner to that describedfor Example 24(a), except that 4-bromo-3-methoxy-phenol, prepared asdescribed by Carreno et. al., Syn. Lett., 11, 124142 (1997), was usedinstead of 4-bromo-2-methoxy-5-methyl-phenol in step (vi). ¹H NMR (300MHz, DMSO-d₆) δ 13.52 (s, 1H), 12.98 (s, 1H), 9.63 (s, 1H), 8.44 (d, 1H,J=8.4 Hz), 7.72 (d, 1H, J=6.9 Hz), 7.61 (s, 1H), 7.50 (d, 1H, J=6.9 Hz),7.36 (dd, 1H, J=8.4, 1.5 Hz), 7.18-7.22 (m, 3H), 6.55 (d, 1H, J=2.1 Hz),6.48 (dd, 1H, J=8.1, 2.1 Hz), 3.74 (s, 3H). MS (ES) [m+H]/z calc'd 357,found 357; [m-H]/z calc'd 355, found 355.

Example 24(e):3-1H-Benzoimidazol-2-yl-6-(2-ethyl-4-hydroxyphenyl)-1H-indazole

[0363]

[0364] Example 24 (e) was prepared in a similar manner to that describedfor Example 24(a), except that 4-bromo-3-ethyl-phenol, prepared in 80%yield according to the procedure described by Carreno et. al., Syn.Lett., 11, 1241-42 (1997) for the synthesis of 4-bromo-3-methyl-phenol,was used instead of 4-bromo-2-methoxy-5-methyl-phenol in step (vi). ¹HNMR (300 MHz, DMSO-d₆) δ 13.66 (s, 1H), 13.02 (s, 1H), 9.43 (s, 1H),8.49 (d, 1H, J=8.4 Hz), 7.72 (d, 1H, J=6.9 Hz), 7.53 (d, 1H, J=6.9 Hz),7.44 (s, 1H), 7.18-7.25 (m, 3H), 7.06 (d, 1H, J=8.1 Hz), 6.75 (d, 1H,J=2.1 Hz), 6.66 (dd, 1H, J=8.1, 2.1 Hz), 2.50 (q, 2H, J=7.5 Hz), 1.04(t, 3H, J=7.5 Hz). MS (ES) [m+H]/z calc'd 355, found 355; [m-H]/z calc'd353, found 353.

Example 24(f): 3-1H-Benzoiniidazol-2-yl-6-(2,4-dihydroxyphenyl)-1H-indazole

[0365]

[0366] 6-(2-methoxy4-hydroxyphenyl)-3-H-benzoimidazol-2-yl-1H-indazole,prepared in example 24(d), (46 mg, 0.13 mmol) was heated in pyridiniumchloride (0.5 g) at 180° C. for 2 h. The reaction was allowed to cool,and was quenched with sat. NaHCO₃ (15 mL) and extracted with EtOAc (2×20mL). Organics were dried (Na₂SO₄) and concentrated in vacuo.Purification by silica gel chromatography (60% THF/hexanes) gave 26 mg(59%) of the title compound as a white solid. ¹H NMR (300 MHz, DMSO-d₆)δ 13.49 (s, 1H), 12.94 (s, 1H), 9.49 (s, 1H), 9.39 (s, 1H), 8.43 (d, 1H,J=8.4 Hz), 7.71-7.74 (m, 2H), 7.50 (d, 1H, J=6.9 Hz), 7.43 (dd, 1H,J=8.4, 1.2 Hz), 7.16-7.23 (m, 3H), 6.45 (d, 1H, J=2.1 Hz), 6.35 (dd, 1H,J=8.4, 2.1 Hz). MS (ES) [m+H]/z calc'd 343, found 343; [m-H]/z calc'd341, found 341.

Example 24(g):3-1H-Benzoimidazol-2-yl-6-(2-phenoxy-4-hydroxyphenyl)-1H-indazole

[0367]

[0368] Example 24 (g) was prepared in a similar manner to that describedfor Example 24(c), except that 3-phenoxy-phenol was used instead of2-chloro-5-methyl-phenol in step (i). ¹H NMR (300 MHz, DMSO-d₆) δ 13.54(s, 1H), 12.95 (s, 1H), 9.78 (s, 1H), 8.43 (d, 1H, J=8.4 Hz), 7.67-7.72(m, 2H), 7.49 (dd, 1H, J=6.3,2.1 Hz), 7.43 (d, 2H, J=8.4 Hz),7.33 (t,2H, J=7.5 Hz), 7.17-7.22 (m, 2H), 6.96-7.07 (m, 3H), 6.72 (dd, 1H,J=8.4,2. 1 Hz), 6.40 (d, 1H, J=2. 1 Hz). MS (ES) [m+H]/z calc'd 419,found 419; [m-H]/z calc'd 417, found 417.

Example 24(h):3-1H-Benzoinidazol-2-yl-6-(2-(2-methoxyethyl)4-hydroxyphenyl)-1H-indazole

[0369]

[0370] Example 24 (h) was prepared in a similar manner to that describedfor Example 24(a), except that{2-[4-bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]-ethyl}-trimethyl-silane,prepared as described below, was used instead of[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethylsilane instep (vii). ¹H NMR (300 MHz, DMSO-d₆) δ 13.60 (s, 1H), 13.01 (s, 1H),9.44 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 7.73 (br s, 1H), 7.51 (br s, 1H),7.46 (s, 1H), 7.21 (app d, 3H, J=8.1 Hz), 7.09 (d, 1H, J=8. 1 Hz), 6.78(d, 1H, J=2.4 Hz), 6.70 (dd, 1H, J=8.1, 2.4 Hz), 3.40 (t, 2H, J=7.2 Hz),3.12 (s, 3H), 2.75 (t, 2H, J=7.2 Hz). MS (ES) [m+H]/z calc'd 385, found385; [m-H]/z calc'd 383, found 383.

[0371] The starting material was prepared as follows:

[0372] 4-Bromo-3-(2-hydroxy-ethyl)-phenol was prepared in 88% yield bythe substitution of 3-(2-hydroxy-ethyl)-phenol in the proceduredescribed in Example 10 24(c), step (i). ¹H NMR (300 MHz, CDCl₃) δ 9.56(s, 1H), 7.29 (d, 1H, J=8.7 Hz), 6.74 (d, 1H, J=3.0 Hz), 6.55 (dd, 1H,J=8.7, 3.0 Hz), 4.71 (t, 1H, J=5.4 Hz), 3.52-3.59 (m, 2H), 2.73 (t, 2H,J=7.2 Hz).

[0373] Preparation of2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl] was prepared in65% yield by the substitution of 4-bromo-3-(2-hydroxy-ethyl)-phenol inthe procedure described in Example 24(a), step (vi). ¹H NMR (300 MHz,CDCl₃) δ 7.43 (d, 1H, J=8.7 Hz), 6.97 (d, 1H, J=3.0 Hz), 6.82 (dd, 1H,J=8.7, 3.0 Hz), 5.19 (s, 2H), 3.88 (q, 2H, J=6.6 Hz), 3.74 (t, 2H, J=8.4Hz), 2.99 (t, 2H, J=6.6 Hz), 1.42 (t, 1H, J=6.6 Hz). 0.94 (t, 2H, J=8.4Hz), -0.01 (s, 9H).

[0374]{²-[4-Bromo-3-(2-methoxy-ethyl)-phenoxyrnethoxy]-ethyl]-trimethyl-silane:2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanol (1.9 g,6.0 mmol) was added to a solution of potassium hydroxide (1.35 g, 24mmol) in DMSO (16 mL). Iodomethane (1.12 mL, 18 mmol) was added, and thesolution stirred for 16 h. The reaction was diluted with water (50 mL)and extracted with ether (2×40 mL). Organics were washed with brine (40mL), dried (Na₂SO₄) and concentrated in vacuo. Purification by silicagel chromatography (10% ether/hexanes) gave 1.28 g of{2-[4-bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]-ethyl}-trimethyl-silaneas a clear oil.

[0375]¹H NMR (300 MHz, CDCl₃) δ 7.40 (d, 1H, J=8.7 Hz), 6.96 (d, 1H,J=3.0 Hz), 6.80 (dd, 1H, J=8.7, 3.0 Hz), 5.18 (s, 2H), 3.74 (t, 2H,J=8.4 Hz), 3.60 (t, 2H, J=7.2 Hz), 3.37 (s, 3H), 2.98 (t, 2H, J=7.2 Hz),0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H).

Example 24(i):3-1H-Benzoimidazol-2-yl-6-(2-(2-hydroxyethyl)-4-hydroxyphenyl)-1H-indazole

[0376]

[0377]3-H-Benzoimidazol-2-yl-6-(2-(2-methoxyethyl)-4-hydroxyphenyl)-1H-indazole,from Example 24(i), (99 mg, 0.26 mmol) was dissolved in EtOAc (20 mL)and cooled to −78° C. under argon. Boron tribromide was added dropwise,and the reaction was allowed to stir while warming to r.t over 3 h. Thesolution was diluted with EtOAc (60 mL) and washed with sat NaHCO₃ andbrine (20 mL each). Organics were dried (Na₂SO₄) and concentrated invacuo. Purification by silica gel chromatography (THF) gave 56 mg (59%)of the title compound as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ13.60 (s, 1H), 13.01 (s, 1H), 9.41 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 7.71(br s, I1H), 7.51 (br s, I1H), 7.46 (s, I1H), 7.21 (app d, 3H, J=8.1Hz), 7.08 (d, 1H, J=8.4 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.69 (dd, 1H,J=8.1, 2.1 Hz), 4.57 (br s, 1H), 3.46 (t, 2H, J=7.2 Hz), 2.68 (t, 2H,J=7.2 Hz). MS (ES) [m+H]/z calc'd 371, found 371; [m-H]/z calc'd 369,found 369.

Example 24(j):3-1H-Benzoimidazol-2-yl-6-(2,6-dimethyl-4-hydroxyphenyl)-1H-indazole

[0378]

[0379] Example 24 (j) was prepared in a similar manner to that describedfor Example 24(a), except that 4-bromo-3,5-dimethyl-phenol was usedinstead of 4-bromo-2-methoxy-5-methyl-phenol in step (vi). ¹H NMR (300MHz, DMSO-d₆) δ 13.57 (s 1H), 12.99 (s, 1H), 9.22 (s, 1H), 8.52 (d, 1H,J=8.4 Hz), 7.72 (d, 1H, J=6.6 Hz), 7.51 (d, 1H, J=6.6 Hz), 7.31 (s, 1H),7.16-7.25 (m, 2H), 7.02 (d, 1H, J=8.4 Hz), 6.55 (s, 2H), 1.93 (s, 6H).MS (ES) [m+H]/z calc'd 355, found 355; [m-H]/z calc'd 353, found 353.

Example 24(k):3-1H-Benzoimidazol-2-yl-6-(2-methylsulfanyl-4-hydroxyphenyl)-1H-indazole

[0380]

[0381] Example 24 (k) was prepared in a similar manner to that describedfor Example 24(c), except that 3-methylsulfanyl-phenol, prepared asdescribed below, was used instead of 2-chloro-5-methyl-phenol in step(i). ¹H NMR (300 MHz, DMSO-d₆) δ 13.59 (s, I1H), 12.98 (s, 1H), 9.64 (s,1H), 8.48 (d, 1H, J=8.4 Hz), 7.71 (br s, 1H), 7.52 (app s, 2H),7.20-7.27 (m, 3H), 7.12 (d, 1H, J=8.4 Hz), 6.76 (d, 1H, J=2. 1 Hz), 6.65(dd, 1H, J=8.4, 2.1 Hz), 2.34 (s, 3H). MS (ES) [m+H]/z calc'd 373, found373; [m-H]/z calc'd 371, found 371.

[0382] The starting material was prepared as follows:

[0383] Preparation of 3-methylsulfanyl-phenol. 3-Hydroxythiophenol (5.0g, 39.7 mmol) and potassium carbonate (6.03 g, 43.6 mmol) were stirredin acetone (80 mL) at 0° C. Iodomethane (2.5 mL, 40 mmol) was addeddropwise, and the reaction stirred for 45 min. The solution was dilutedwith H₂O (150 mL) and extracted with EtOAc (2×100 mL). Organics werewashed with brine (100 mL), dried (Na₂SO₄) and concentrated in vacuo.Purification by silica gel chromatography (25% EtOAc/hexanes) 5.08 g(91%) of 3-methylsulfanyl-phenol as a clear oil. ¹H NMR (300 MHz, CDCl₃)δ 7.15 (t, 1H, J=8.1 Hz), 6.82 (d, 1H, J=8.1 Hz), 6.74 (t, 1H, J=1.8Hz), 6.60 (dd, 1H, J=8.1, 1.8 Hz), 4.86 (s, 1H), 2.47 (s, 3H).

Example 24(l):3-1H-Benzoimidazol-2-yl-6-(2-(ethoxymethyl)-5-methoxy-4-hydroxy-phenyl)-1H-indazole

[0384]

[0385] Example 24 (1) was prepared in a similar manner to that describedfor Example 24(a), except that[2-(4-bromo-5-ethoxymethyl-2-methoxy-phenoxymethoxy)-ethyl]-trimethyl-silane,prepared as described below, was used instead of[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethylsilane instep (vii). ¹H NMR (300 MHz, DMSO-d₆) δ 13.63 (s, 1H), 12.99 (s, 1H),9.15 (s, 1H), 8.50 (d, 1H, J=8.4 Hz), 7.73 (dd, 1H, J=6.6, 2.1 Hz), 7.59(s, 1H), 7.51 (dd, 1H, J=6.6, 2.1 Hz), 7.32 (d, 1H, J=8.4 Hz), 7.19-7.24(m, 2H), 6.94 (s, 1H), 6.91 (s, 1H), 4.22 (s, 2H), 3.81 (s, 3H), 3.39(q, 2H, J=6.9 Hz), 1.13 (t, 3H, J=6.9 Hz). MS (ES) [m+H]/z calc'd 415,found 415.

[0386] The starting material was prepared as follows:

[0387]2-Bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde wasprepared in 79% yield by the substitution of4-bromo-3-formyl-2-methoxy-phenol (Hazlet et. al., J. Org. Chem., 27,3253-55 (1962)) in the procedure described in Example 24(a), step (vi).¹H NMR (300 MHz, CDCl₃) δ 10.16 (s, 1H), 7.68 (s, 1H), 7.07 (s, 1H),5.28 (s, 2H), 3.94 (s, 3H), 3.77 (t, 2H, J=8.4 Hz), 0.94 (t, 2H, J=8.4Hz), −0.03 (s, 9H).

[0388] Preparation of[2-(4-Bromo-5-ethoxymethyl-2-methoxy-phenoxymethoxy)-ethyl]-trimethyl-silane:Sodium borohydride (275 mg, 7.2 mmol) was added in portions over 10 minto a solution of2-bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde (1.3g, 3.6 mmol) in MeOH (20 mL) at 0° C. After 30 min, the reaction wasdiluted with H₂O (40 mL) and extracted with EtOAc (2×30 mL). Organicswere washed with brine (30 mL), dried (Na₂SO₄) and concentrated in vacuoto give 1.31 g of [2-bromo4-methoxy-5-(2trimethylsilanyl-ethoxmethoxy)-phenyl]-methanol as a clear oil. ¹H NMR(300 MHz, CDCl₃) δ 7.29 (s, 1H), 7.05 (s, 1H), 5.27 (s, 2H), 4.66 (d,2H, J=6.6 Hz), 3.87 (s, 3H), 3.79 (t, 2H, J=8.4 Hz), 1.92 (t, 1H, J=6.6Hz), 0.96 (t, 2H, J=8.4 Hz), 0.01 (s, 9H).

[0389] The crude benzyl alcohol was stirred with a solution of potassiumhydroxide (800 mg, 14.4 mmol) in DMSO (8 mL). lodoethane (580 mL, 7.2mmol) was added, and the reaction stirred for 16 h before it was dilutedwith H₂O (30 mL) and extracted with ether (2×30 mL). Organics werewashed with brine (20 mL), dried (Na₂SO₄) and concentrated in vacuo.Purification by silica gel chromatography (15% EtOAc/hexanes) gave 1.30g (92%) of the title compound as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ7.29 (s, 1H), 7.03 (s, 1H), 5.26 (s, 2H), 4.48 (s, 2H), 3.85 (s, 3H),3.79 (t, 2H, J=8.4 Hz), 3.58 (q, 2H, J=6.9 Hz), 1.26 (t, 3H, J=6.9 Hz),0.95 (t, 2H, J=8.4 Hz), -0.01 (s, 9H).

Example 24(m): 3-1H-Benzoimidaz1-2-yl-6-(2-(hydroxymethyl)-4-ethoxy-5-methoxy-phenyl)- 1H-indazole

[0390]

[0391] Example 24 (m) was prepared in a similar manner to that describedfor Example 24(a), except that[2-(2-bromo-5-ethoxy-4-methoxy-benzyloxymethoxy)-ethyl]-trimethyl-silane,prepared as described below, was used instead of[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethylsilane instep (vii). ¹H NMR (300 MHz, DMSO-d₆) δ 13.64 (s, 1H), 13.00 (s, 1H),8.50 (d, 1H, J=8.4 Hz), 7.73 (d, 1H, J=8.4 Hz), 7.62 (s, 1H), 7.52 (dd,1H, J=6.0, 1.8 Hz), 7.32 (dd, 1H, J=8.4, 1.2 Hz), 7.19-7.24 (m, 2H),7.15 (s, 1H), 6.91 (s, 1H), 5.11 (t, 1H, J=5.1 Hz), 4.37 (d, 2H, J=5. 1Hz), 4.08 (q, 2H, J=6.9 Hz), 3.80 (s, 3H), 1.37 (t, 3H, J=6.9 Hz). MS(ES) [m+H]/z calc'd 415, found 415.

[0392] The starting material was prepared as follows:

[0393] Preparation of4-bromo-2-methoxy-5-(2-trimethylsilanyl-ethoxymethyl)-phenol:[2-Bromo4-methoxy-5-(2-trimethylsilanyl-ethoxmethoxy)-phenyl]-methanol,upon sitting for periods of over a week, underwent SEM-migration fromthe phenolic to the benzylic alcohol to yield the title compound. ¹H NMR(300 MHz, CDCl₃) δ 7.04 (s, 1H), 7.01 (s, 1H), 5.54 (s, 1H), 4.77 (s,2H), 4.57 (s, 2H), 3.88 (s, 3H), 3.68 (t, 2H, J=8.4 Hz), 0.97 (t, 2H,J=8.4 Hz), 0.02 (s, 9H).

[0394] Preparation of[2-(2-bromo-5-ethoxy-4-methoxy-benzyloxymethoxy)-ethyl]-trimethyl-silane:4-Bromo-2-methoxy-5-(2-trimethylsilanyl-ethoxymethyl)-phenol (1.28 g,3.53 mmol) was stirred with a solution of potassium hydroxide (790 mg,14.1 mmol) in DMSO (8 mL). Iodoethane (565 mL, 7.1 mmol) was added, andthe reaction stirred for 16 h before it was diluted with H₂O (30 mL) andextracted with ether (2×30 mL). Organics were washed with brine (20 mL),dried (Na₂SO₄) and concentrated in vacuo. Purification by silica gelchromatography (15% EtOAc/hexanes) gave 1.26 g (91%) of the titlecompound as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.02 (s, 1H), 6.98(s, 1H), 4.78 (s, 2H), 4.60 (s, 2H), 4.09 (q, 2H, J=6.6 Hz), 3.86 (s,3H), 3.69 (t, 2H, J=8.4 Hz), 1.46 (t, 3H, J=6.6 Hz), 0.97 (t, 2H, J=8.4Hz), 0.04 (s, 9H).

Example 24(n):3-1H-Benzoimidazol-2-yl-6-(2-(hydroxymethyl)-5-methoxy-4-hydroxy-phenyl)-1H-indazole

[0395]

[0396] Example 24 (ri) was prepared in a similar manner to thatdescribed for Example 24(a), except that6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole,prepared as described below, was used instead of6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole.¹H NMR (300 MHz, DMSO-d₆) δ 13.59 (s, 1H), 12.95 (s, 1H), 9.05 (s, 1H),8.49 (d, 1H, J=8.4 Hz), 7.72 (dd, 1H, J=6.3, 2.1 Hz), 7.60 (s, 1H), 7.51(dd, 1H, J=6.3, 2.1 Hz), 7.31 (d, 1H, J=8.4 Hz), 7.20-7.24 (m, 2H), 7.02(s, 1H), 6.87 (s, 1H), 5.02 (t, 1H, J=5.4 Hz), 4.32 (d, 2H, J=5.4 Hz),3.80 (s, 3H). MS (ES) [m+H]/z calc'd 387, found 387; [m-H]/z calc'd 385,found 385.

[0397] The starting material was prepared as follows:

[0398] Preparation of⁴-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-benzaldehyde:2-Bromo4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde (3.36g, 9.3 mmol) and hexamethylditin (5.0 g, 15.3 mmol) were stirred in drytoluene (60 mL) in a flask purged with argon.

[0399] Tetrakis(triphenylphosphine)palladium(0) (500 mg, 0.45 mmol) wasadded, and the reaction stirred at 100° C. for 23 h. The reaction wascooled and concentrated in vacuo. Purification by silica gelchromatography (5% EtOAc/hexanes) gave 2.77 g (67%) of4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-benzaldehydeas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 9.81 (dd, 1H, J=3.0, 0.9 Hz),7.66 (t, 1H, J=6.6 Hz), 7.21 (t, 1H, J=9.0 Hz), 5.35 (s, 2H), 3.99 (s,3H), 3.82 (t, 2H, J=8.4 Hz), 0.25 (t, 9H, J=26.7 Hz), 0.98 (t, 2H, J=8.4Hz), -0.01 (s, 9H).

[0400] Preparation of[4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanol:4-Methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-benzaldehyde(2.36 g, 5.3 mmol) was stirred in MeOH (30 mL) at 0° C. Sodiumborohydride (400 mg, 10.6 mmol) was added, and the reaction stirred for1 h. The solution was diluted with H₂O (60 mL), and extracted with EtOAc(2×50 mL). Organics were washed with brine (50 mL), dried (Na₂SO₄), andconcentrated in vacuo to give 2.16 g (91%) of[4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanolas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.18 (t, 1H, J=6.9 Hz), 7.03(t, 1H, J=9.3 Hz), 5.27 (s, 2H), 4.58-14.63 (m, 2H), 3.89 (s, 3H), 3.80(t, 2H, J=8.4 Hz), 1.53 (t, 1H, J=6.0 Hz), 0.96 (t, 2H, J=8.4 Hz), 0.31(t, 9H, J=27.3 Hz), 0.01 (s, 9H).

[0401] Preparation of6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole:6-Iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-H-benzoimidazol-2-yl}-1H-indazole[Example 24(a), step (v)] (300 mg, 0.48 mmol) and[4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanol(282 mg, 0.63 mmol) were stirred in dioxane (8 mL) under argon at 98° C.for 16 h. The reaction was allowed to cool and was diluted with EtOAc.Organics were washed with sat NaHCO₃ and brine, dried (Na₂SO₄), andconcentrated in vacuo. Purification by silica gel chromatography (20%EtOAc/hexanes) gave 224 mg (60%) of6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(²-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazolas a faint yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, I1H, J=8.4Hz), 7.89-7.92 (m, 1H), 7.63-7.66 (m, 2H), 7.34-7.41 (m, 4H), 6.91 (s,1H), 6.29 (s, 2H), 5.83 (s, 2H), 5.36 (s, 2H), 4.55 (s, 2H), 3.78-3.92(m, 5H), 3.59-3.70 (m, 4H), 0.83-1.04 (m, 6H), 0.03 (s, 9H);-0.04 (s,9H), -0.13 (s, 9 Hz).

Example 24(o): 3-1H-Benzoimidazol-2-yl-6-(3-hydroxyphenyl)-1H-indazole

[0402]

[0403] Example 24 (o) was prepared in a similar manner to that describedfor Example 24(f), except that6-(3-methoxy-phenyl)-3-H-benzoimidazol-2-yl-1H-indazole, prepared in asimilar manner to that described for example 24(a) except that3-methoxy-phenylboronic acid was used instead of5-methoxy-2-methyl-4-[2-(trimethylsilanyl)-ethoxymethoxy]-phenylboronicacid in step (viii), was used instead of6-(2-methoxy4-hydroxyphenyl)-3-1H-benzoimidazol-2-yl-1H-indazole. ¹H NMR(300 MHz, DMSO-d₆) δ 13.67 (s, 1H), 13.00 (s, 1H), 9.58 (s, 1H), 8.55(d, 1H, J=8.4 Hz), 7.71-7.75 (m, 2H), 7.49-7.57 (m, 2H), 7.30 (t, 1H,J=7.8 Hz), 7.12-7.24 (m, 4H), 6.80 (dd, 1H, J=8.1, 1.5 Hz). MS (ES)[m+H]/z calc'd 327, found 327; [m-H]/z calc'd 325, found 325.

Example 24(p):3-1H-Benzoimidazol-2-yI-6-(2-methoxy-3-hydroxyphenyl)-1H-indazole

[0404]

[0405] Example 24 (p) was prepared in a similar manner to that describedfor Example 24(a), except that 3-bromo-2-methoxy-phenol, prepared asdescribed by Aristoff et.al., Tet. Lett., 25, 3955-58 (1984) was usedinstead of 4-bromo-2-methoxy-5-methyl-phenol in step (vi). ¹H NMR (300MHz, DMSO-d₆) δ 13.60 (s, 1H), 12.97 (s, 1H), 9.37 (s, 1H), 8.52 (d, 1H,J=8.4 Hz), 7.69-7.74 (m, 2H), 7.51 (dd, 1H, J=7.8, 1.8 Hz), 7.43 (dd,1H, J=8.4, 1.2 Hz), 7.19-7.24 (m, 2H), 7.02 (t, 1H, J=7.8 Hz), 6.85-6.93(m, 2H), 3.50 (s, 3H). MS (ES) [m+H]/z calc'd 357, found 355, [m-H]/zcalc'd 357, found 355.

Example 25(a):3-(3H-Imidazo[4,5-c]pyridin-2-yl)-6-(4-hydroxy-2-methoxyphenyl)-1H-indazole

[0406]

[0407] A solution of of6-[5-methoxy--2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1H-indazole(68 mg, 0.11 mmol) in TBAF (1 M in THF, 1.2 mL, 1.2 mmol) withethylenediamine (150 mL, 2.2 mmol) was stirred at 68° C. for 48 h. Thesolution was concentrated in vacuo and purified by silica gelchromatography (2:1 EtOH/EtOAc). Precipitation from acetonitrile gave 21mg (53%) of3-(3H-imidazo[4,5-c]pyridin-2-yl)-6-(4-hydroxy-2-methoxyphenyl)-1H-indazoleas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.70 (s, 1H), 13.49 (brs, 1H), 9.62 (s, 1H), 9.01 (br s, 1H), 8.43 (d, 1H, J=8.7 Hz), 8.34 (d,1H, J=5.7 Hz), 7.64(s, 1H),7.57(brs, 1H),7.39(dd, 1H,J=8.7, l.5 Hz),7.21(d, 1H,J=8.1 Hz), 6.55 (d, 1H, J=2.1 Hz), 6.49 (dd, 1H, J=8.1, 2.1 Hz),3.74 (s, 3H). MS (ES) [m+H]/z calc'd 358, found 358; [m-H]/z calc'd 356,found 356.

[0408] The intermediates were prepared as follows:

[0409]3-(1,1-Dimethoxy-methyl)-6-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole.A solution of6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole[Example 14, step (i)] (1.28 g, 2.69 mmol) in CH₂Cl₂ (4OmL)/MeOH (40 mL)was stirred at −78° C. The reaction was treated with ozone until a bluecolor persisted, and then was purged with argon. Methyl sulfide (4 mL)was added, and the reaction stirred 4 h while warming to r.t.Concentration in vacuo gave a crude mixture of acetal and aldehyde,which was converted completely to the acetal by stirring in trimethylorthoformate (10 mL) with Amberlyst 15(wet) acidic ion-exchange resin(0.8 g) for 1 h. The resin was removed by filtration, and the solutionwas concentrated in vacuo. Purification by silica gel chromatographygave 1.11 g (92%) of3-(1,1-dimethoxy-methyl)-6-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.98 (s, 1H), 7.68 (d, 1H,J=8.4 Hz), 7.48 (dd, 1H, J=8.4, 1.2 Hz), 5.77 (s, 1H), 5.69 (s, 2H),3.53 (t, 2H, J=8.4 Hz), 3.43 (s, 6H), 0.88 (t, 2H, J=8.4 Hz), -0.06 (s,9H).

[0410]3-(1,1-Dimethoxy-methyl)-6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole.3-(1,1-Dimethoxy-methyl)-6-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(1.06 g, 2.37 mmol),²-methoxy4-(trimethylsilanyl-ethoxymethoxy)-phenylboronic acid (0.99 g,3.32 mmol), and sodium carbonate (352 mg, 1.4 mmol) were stirred in amixture of benzene (15 mL), MeOH (3 mL), and water (1 mL) in a flaskpurged with argon. Tetrakis(triphenylphosphine)palladium(0) (220 mg,0.19 mmol) was added, and the reaction stirred at reflux for 16 h. Thereaction was allowed to cool and was diluted with ether (70 mL).Organics were washed with H₂O and brine (30 mL each), dried (Na₂SO₄),and concentrated in vacuo. Purification by silica gel chromatography(15% EtOAc/hexanes) gave 1.12 g (82%) of3-(1,1-dimethoxy-methyl)-6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas a faintly yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, 1H, J=8.4Hz), 7.64 (s, 1H), 7.37 (dd, 1H, J=8.4, 1.2 Hz), 7.29 (d, 1H, J=8.4 Hz),6.71-6.77 (m, 2H), 5.82 (s, 1H), 5.75 (s, 2H), 5.28 (s, 2H), 3.77-3.83(m, 5H), 3.57 (t, 2H, J=8.4 Hz), 3.46 (s, 6H), 1.00 (t, 2H, J=8.4 Hz),0.88 (t, 2H, J=8.4 Hz), 0.03 (s, 9H), −0.05 (s, 9H).

[0411]6-[2-Methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde.3-(1,1-Dimethoxy-methyl)-6-[2-methoxy4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(1.1 g, 1.92 mmol) was stirred in 1% TFA/CH₂Cl₂ (20 mL) for 1 h at rt.Concentration in vacuo yielded 1.01 g (100%) of6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydeas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 10.27 (s, 1H), 8.28 (d, 1H,J=8.4 Hz), 7.73 (s, 1H), 7.55 (dd, 1H, J=8.4, 1.2 Hz), 7.29 (d, 1H,J=8.4 Hz), 6.72-6.79 (m, 2H), 5.82 (s, 2H), 5.28 (s, 2H), 3.78-3.84 (m,5H), 3.61 (t, 2H, J=8.1 Hz), 0.89-1.03 (m, 4H), 0.03 (s, 9H), -0.05 (s,9H).

[0412]6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1H-indazole.6-[2-Methoxy-4-(2-trimethyl-silanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde(320 mg, 0.61 mmol), 3,4-diamino-pyridine (68 mg, 0.62 mmol), and sulfur(23 mg, 0.73 mmol) were combined in dry DMF (2 mL) and stirred at 90° C.for 16 h under argon. The reaction was allowed to cool and was dilutedwith EtOAc (20 mL). Organics were washed with sat. NaHCO₃ and brine (15mL each), dried (Na₂SO₄), and concentrated in vacuo. Purification bysilica gel chromatography (75% to 100% EtOAc/hexanes) gave 78 mg (21%)of6-[5-methoxy--2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1H-indazoleas a white solid. ¹H NMR (300 MHz, CDCl₃) δ 10.69 (br s, 1H), 9.21 (s,1H), 8.63 (dd, 1H J=8.4, 0.3 Hz), 8.50 (d, 1H, J=5.4 Hz), 7.73 (s, 1H),7.47 (br s, 1H), 7.57 (dd, 1H, J=8.7, 1.2 Hz), 7.33 (d, 1H, J=8.4 Hz),6.74-6.80 (m, 2H), 5.80 (s, 2H), 5.29 (s, 2H), 3.78-3.85 (m, SH), 3.63(t, 2H, J=8.1 Hz), 0.89-1.04 (m, 4H), 0.04 (s, 9H), -0.06 (s, 9H).

Example 25(b):3-[6-(2-morpholin-4-yl-ethylcarbamoyl)-1H-benzoimidazol-2-yl]-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

[0413]

[0414] Example 25 (b) was prepared in a similar manner to that describedfor Example 25(a), except that3,4-diamino-N-(2-morpholin4-yl-ethyl)-benzamide, prepared as describedbelow, was used instead of 3,4-diaminopyridine in step (iv). ¹H NMR (300MHz, DMSO-d₆) δ 13.61 (s, 0.5H), 13.59 (s, 0.5H), 13.22 (s, 0.5H), 13.18(s, 0.5H), 9.59 (s, 1H), 8.35-8.46 (m, 2H), 8.27 (s, 0.5H), 8.02 (s,0.5H), 7.71-7.79 (m, 1.SH), 7.63 (s, 1H), 7.53 (d, 0.5H, J=8.7 Hz), 7.38(d, 1H, J=8.7 Hz), 7.21 (d, 1H, J=8.7 Hz), 6.55 (d, 1H, J=2.1 Hz), 6.49(dd, 1H, J=8.4, 2.1 Hz),3.75 (s, 3H), 3.58 (t, 4H, J=4.5 Hz), 3.42 (q,2H, J=6.0 Hz), 2.43-2.51 (m, 6H). MS (ES) [m+H]/z calc'd 513, found 513;[m-H]/z calc'd 511, found 511.

[0415] 3,4-Diamino-N-(2-morpholin4-yl-ethyl)-benzamide was prepared asfollows:

[0416] 3,4-Diamino-N-(2-morpholin-4-yl-ethyl)-benzamide.3,4-Diaminobenzoic acid (5 g, 32.9 mmol), 4-(2-aminoethyl)morpholine(5.2 mL, 39.4 mmol), triethylamine (9.2 mL, 66 mmol), and DMAP (0.40 g,3.3 mmol) were combined in dry DMF (80 mL) at 0° C. EDC (9.45 g, 49.3mmol) was added, and the reaction stirred for 24 h at r.t. Concentrationin vacuo and purification by silica gel chromatography (10% MeOHICH₂Cl₂with 0.2% NH₄OH) gave 2.6 g (31%) of3,4-diamino-N-(2-morpholin-4-yl-ethyl)-benzamide as a light brown solid.¹H NMR (300 MHz, DMSO-d₆) δ 7.72 (t, 1H, J=5.4 Hz), 7.02 (d, 1H, J=1.8Hz), 6.92 (dd, 1H, J=8.1, 1.8 Hz), 6.46 (d, 1H, J=8.1 Hz), 4.89 (br s,2H), 4.51 (br s, 2H), 3.55 (t, 4H, J=4.8 Hz), 3.29 (q, 2H, J=7.2 Hz),2.36-2.43 (m, 6H).

Example 25(c):3-[6-(4-methylpiperazin-1-yI)-1H-benzoimidazol-2-yl]-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

[0417]

[0418] Example 25 (c) was prepared in a similar manner to that describedfor Example 25(a), except4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine (Harapanhalli et al., J.Med. Chem., 39,4804-09 (1996)) was used instead of 3,4-diaminopyridinein step (iv). ¹H NMR (300 MHz, DMSO-d₆) δ 13.51 (s, 0.33H), 13.38 (s,0.67H), 12.66 (s, 0.33H), 12.59 (s, 0.67H), 9.58 (s, 1H), 8.42 (d,0.33H, J=8.4 Hz), 8,41 (d, 0.67H, J=8.4 Hz), 7.59 (s, 1H), 7.55 (d,0.67H, J=8.7 Hz), 7.31-7.37 (m, 1.33H), 7.20 (app d, 1.33H, J=8.4 Hz),6.92-7.01 (m, 1.67H), 6.55 (d, 1H, J=1.5 Hz), 6.48 (dd, 1H, J=8.4, 2.1Hz), 3.74 (s, 3H), 3.12 (br s, 4H), 2.50 (br s, 4H), 2.22 (s, 3H). MS(ES) [m+H]/z calc'd 455, found 455; [m-H]/z calc'd 453, found 453.

Example 25(d):3-[4-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

[0419]

[0420] Example 25 (d) was prepared in a similar manner to that describedfor Example 25(a), except 3-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine (Harapanhalli et al., J. Med. Chem., 39, 4804-09 (1996)),analogous to the 4-isomer preparation) was used instead of3,4-diaminopyridine in step (iv). 1H NMR (300 MHz, DMSO-d₆) δ 13.41 (brs, 1H), 12.79 (br s, 1H), 9.60 (br s, 1H), 8.37 (d, 1H, J=8.4 Hz), 7.60(s, 1H), 7.36 (dd, 1H, J=8.4,1.2 Hz), 7.22 (d, 1H, J=8.4 Hz), 7.03-7.07(m, 2H), 6.46-6.56 (m, 3H), 3.75 (s, 3H), 3.62 (br s, 4H), 2.62 (br s,4H), 2.28 (s, 3H). MS (ES) [m+H]/z calc'd 455, found 455; [m-H]/z calc'd453, found 453.

Example 25(e): 3-imidazol-2-yl-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

[0421]

[0422] Example 25(e) was prepared in a similar manner to that describedfor Example 25(a), except6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-imidazol-2-yl-1H-indazolewas used instead of6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-]pyridin-2-yl]-1H-indazole.¹H NMR (300 MHz, DMSO-d₆) δ 13.10 (s, 1H), 12.59 (s, 1H), 9.56 (s, 1H),8.27 (d, 1H, J=8.4 Hz), 7.53 (s, 1H), 7.25 (dd, 1H, J=8.4, 1.2 Hz),7.13-7.20 (m, 3H), 6.54 (d, 1H, J=2.1 Hz), 6.47 (dd, 1H, J=8.4, 2.1 Hz),3.73 (s, 3H). MS (ES) [m+H]/z calc'd 307, found 307.

[0423] The starting material was prepared as follows:

[0424] Glyoxal (40 wt % in H₂O, 0.4 mL, 3.5 mmol) was added dropwise toa solution of 420 mg (0.8 mmol)⁶-[²-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde,from Example 25(a) step (iii), and 28% aqueous ammonia (0.6 mL) in THF(8 mL)/MeOH (8 mL), and the solution was stirred at r.t. for 16 h. Thereaction was concentrated in vacuo and dissolved in CHCl₃ (50 mL).Organics were washed with H₂O and brine (25 mL each), dried (Na₂SO₄) andconcentrated in vacuo. Purification by silica gel chromatography (40%EtOAc/hexanes) gave 120 mg (27%) of6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-imidazol-2-yl-1H-indazoleas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 10.03 (s, 1H), 8.48 (d, 1H,J=8.4 Hz), 7.65 (s, 1H), 7.46 (dd, 1H, J=8.4, 1.5 Hz), 7.29-7.48 (m,2H), 7.13 (d, 1H, J=1.5 Hz), 6.73-6.78 (m, 2H), 5.73 (s, 2H), 5.28 (s,2H), 3.78-3.86 (m, 5H), 3.60 (t, 2H, J=8.4 Hz), 0.88-1.03 (m, 4H), 0.03(s, 9H), -0.05 (s, 9H).

Example 25(f):3-[4-(2-hydroxyethylsulfanyl)-1H-benzoimidazol-2-yl]-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

[0425]

[0426] Example 25 (f) was prepared in a similar manner to that describedfor Example 25(a), except that 2-(2,3-diamino-phenylsulfanyl)-ethanol)was used instead of 3,4-diaminopyridine in step (iv). ¹H NMR (300 MHz,DMSO-d₆) δ 13.51 (s, 1H), 13.02 (s, 1H), 9.59 (s, 1H), 8.45 (d, 1H,J=8.4 Hz), 7.61 (s, 1H), 7.32-7.40 (m, 2H), 7.11-7.23 (m, 3H), 6.55 (d,1H, J=2.4 Hz), 6.48 (dd, 1H, J=8.1, 2.4 Hz), 4.96 (br s, 1H), 3.75 (s,3H), 3.65 (br s, 2H), 3.33 (t, 2H, J=6.9 Hz). MS (ES) [m+Na]/z calc'd455, found 455, [m-H]/z calc'd 431, found 431.

[0427] The starting material was prepared as follows:

[0428] 2-(3-Amino-2-nitro-phenylsulfanyl)-ethanol.3-Chloro-2-nitro-aniline (1.12 g, 6.5 mmol), 2-mercaptoethanol (0.60 ml,8.6 mmol), and potassium carbonate (0.99 g, 7.1 mmol) were combined indry DMF (15 ml) and stirred at 130° C. for 4 h. The solution was allowedto cool and was concentrated in vacuo. Purification by silica gelchromatography (70% EtOAc/hexanes) gave 1.29 g (93%) of2-(3-amino-2-nitro-phenylsulfanyl)-ethanol as a bright red solid. ¹H NMR(300 MHz, DMSO-d₆) δ 7.20 (t, 1H, J=8.1 Hz), 6.80 (s, 2H), 6.73 (dd, 1H,J=8.4, 0.9 Hz), 6.63 (dd, 1H, J=7.8, 1.2 Hz), 4.92 (t, 1H, J=6.0 Hz),3.58 (q, 2H, J=6.0 Hz), 2.98 (t, 2H, J=6.0 Hz).2-(2,3-Diamino-phenylsulfanyl)-ethanol.2-(3-Amino-2-nitro-phenylsulfanyl)-ethanol (1.02 g, 4.8 mmol) wasreduced by hydrogenation using 45 psi of H₂ with 10% Pd-C (180 mg) inEtOAc (25 mL) for 6 h. After filtering through Celite, solvent wasremoved in vacuo. Purification by silica gel chromatography (EtOAc) gave762 mg (87%) of 2-(2,3-diamino-phenylsulfanyl)-ethanol as a faintlyyellow solid. ¹H NMR (300 MHz, CDCl₃) δ 6.98 (dd, 1H, J=7.5, 1.5 Hz),6.60-6.72 (m, 2H), 3.65 (t, 2H, J=5.7 Hz), 3.55 (br s, 5H), 2.91 (t, 2H,J=5.7 Hz).

Example 25(g):3-(5-methylcarbamoyl-1H-benzoiniidazol-2-yl)-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

[0429]

[0430] Example 25 (g) was prepared in a similar manner to that describedfor Example 25(a), except 3,4-diamino-N-methyl-benzamide (Kumar, et. al.J. Med. Chem., 27, 1083-89 (1984)) was used instead of3,4-diaminopyridine in step (iv). ¹H NMR (300 MHz, DMSO-d₆) δ 13.59 (s,0.5H), 13.55 (s, 0.5H), 13.21 (s, 0.5H), 13.14 (s, 0.5H), 9.60 (s, 1H),8.38-9.46 (m, 2H), 8.26 (s, 0.5H), 8.03 (s, 0.5H), 7.71-7.79 (m, 1.5H),7.63 (s, 1H), 7.52 (d, 0.5H, J=8.4 Hz), 7.35-7.40 (m, 1H), 7.21 (d, 1H,J=2.1 Hz), 6.55 (d, 1H, J=2.4 Hz), 6.49 (dd, 1H, J=8.4, 2.4 Hz), 3.75(s, 3H), 2.82 (d, 1.5H, J=1.5 Hz), 2.81 (d, 1.5H, J=1.5 Hz). MS (ES)[m+H]/z calc'd 414, found 414, [m-H]/z calc'd 412, found 412.

Example 25(h):3-(5-Dimethylamino-1H-benzoimidazol-2-yl)-6-(2-methoxy-4-hydroxy-phenyl)-1H-indazole

[0431]

[0432] Example 25 (h) was prepared in a similar manner to that describedfor Example 25(a), 15 except 3,4-diamino-N,N-dimethyl-aniline (Cazaux,et. al., Can. J. Chem., 71, 1236-46 (1993)) was used instead of3,4-diaminopyridine in step (iv). ¹H NMR (300 MHz, DMSO-d₆) δ 13.36 (s,1H), 12.51 (br s, 1H), 9.58 (s, 1H), 8.42 (d, 1H, J=8.4 Hz), 7.59 (s,1H), 7.49 (br s, 1H), 7.33 (dd, 1H, J=8.4,1.2 Hz), 7.20 (d, 1H, J=8.1Hz), 6.87 (br d, 2H, J=8.1 Hz), 6.55 (d, 1H, J=2.1 Hz), 6.48 (dd, 1H,J=8.1, 2.1 Hz), 3.73 (s, 3H), 2.92 (s, 6H). MS (ES) [m+H]/z calc'd 400,found 400, [m-HJ/z calc'd 398, found 398.

Example 25(i):3-(5-Aminosulfonyl-1H-benzoimidazol-2-yl)-6-(2-methoxy-4-hydroxy-phenyl)-1H-indazole

[0433]

[0434] Example 25 (i) was prepared in a similar manner to that describedfor Example 25(a), except 3,4-diarnino-benzenesulfonamide was usedinstead of 3,4-diaminopyridine in step (iv). ¹H NMR (300 MHz, DMSO-d₆) δ13.67 (s, 0.5H), 13.64 (s, 0.5H), 13.39 (s, 0.5H), 13.35 (s, 0.5H), 9.60(s, 1H), 8.43 (d, 1H, J=8.1 Hz), 8.18 (d, 0.5H, J=1.5 Hz), 10 7.99 (d,0.5H, J=1.5 Hz), 7.86 (d, 0.5H, J=8.4 Hz), 7.62-7.72 (m, 2.5H), 7.29 (d,1H, J=8.4 Hz), 7.20-7.28 (m, 3H), 6.55 (d, 1 H, J=2. 1 Hz), 6.49 (dd,1H, J=8.4, 2.1 Hz), 3.75 (s, 3H). MS (ES) [m+H]/z calc'd 436, found 436,[m-H]/z calc'd 434, found 434.

Example 25(i):3-(4-methylcarbamoyl-1H-benzoimidazol-2-yl)-6-(2-methoxy-4-hydroxy-phenyl)-1H-indazole

[0435]

[0436] Example 25 (i) was prepared in a similar manner to that describedfor Example 25(a), 2,3-diamino-N-methyl-benzamide was used instead of3,4-diaminopyridine in step (iv). ¹H NMR (300 MHz, DMSO-d₆) δ 13.71 (s,1H), 13.46 (s, 1H), 9.85 (br d, 1H, J=4.8 Hz), 9.61 (s, 1H), 8.38 (d,1H, J=8.4 Hz), 7.89 (dd, 1H, J=7.5, 1.2 Hz), 7.66-7.72 (m, 2H),7.47 (dd,1H, J=8.4, 1.2 Hz), 7.36 (t, 1H, J=7.8 Hz), 7.23 (d, 1H, J=8.1 Hz), 6.56(d, 1H,J=2.4 Hz), 6.50 (dd, 1H,J=8.4,2.4 Hz), 3.76 (s, 3H), 3.10 (d, 3H,J=1.8 Hz). MS (ES) [m+H]/z calc'd 414, found 414, [m-H]/z calc'd 412,found 412.

[0437] 2,3-Diamino-N-methyl-benzamide was prepared as follows:

[0438] 2-Amino-N-methyl-3-nitro-benzamide. 2-Amino-3-nitro-benzoic acid(1.8 g, 9.9 mmol) and methylamine hydrochloride (1.33 g, 19.8 mmol),were stirred in dry CH₂Cl₂ (30 ml)/DMF (5 mL) at 0° C. EDC (2.83 g, 14.8mmol) and DIEA (4.92 mL, 27.7 mmol) were added, and the solution stirred3 h while warming to r.t. The reaction was concentrated in vacuo andpurified by silica gel chromatography (8% MeOHICHCl₃) to give 1.42 g(74%) of 2-amino-N-methyl-3-nitro-benzamide as a yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 8.58 (br s, 1H), 8.23 (br s, 2H), 8.15 (dd, 1H,J=8.1, 1.8 Hz), 7.82 (dd, 1H, J=8.1, 1.8 Hz), 6.68 (t, 1H, J=8. 1 Hz),2.76 (d, 3H, J=4.5 Hz).

[0439] 2,3-Diamino-N-methyl-benzamide.2-Amino-N-methyl-3-nitro-benzamide (1.4 g, 7.2 mmol) was reduced byhydrogenation using 50 psi of H₂ with 10% Pd-C (250 mg) in EtOAc (25 mL)for 5 h. After filtering through Celite, solvent was removed in vacuo.Purification by silica gel chromatography (10% MeOH/CHCl₃) gave 1.08 mg(91%) of 2,3-diamino-N-methyl-benzamide as a faintly yellow solid. ¹HNMR (300 MHz, CDCl₃) δ 6.87 (dd, 1H, J=7.8, 1.5 Hz), 6.76 (dd, 1H,J=7.8, 1.5 Hz), 6.59 (t, 1H, J=7.8 Hz), 6.14 (br s, 1H), 4.28 (br s,4H),2.95 (d, 3H, J=5.1 Hz).

Example 26:6-(4-Hydroxy-3methoxyphenyl)-3-[E-2-(4-glycylamino-phenyl)-ethenyl]-1H-indazole

[0440]

[0441] Example 26 was prepared from the starting material describedbelow in a similar manner to that described for Example 1(a): ¹H NMR(300 MHz, CDCl₃) δ 8.29 (d, 1H), 7.80 (m, 5H), 7.58 (m, 3H), 7.38 (s,H), 7.27 (d, 1H), 7.01 (d, 1H), 4.00 (s, 3H), 3.42 (s, 2H); LCMS (100%area) Rt=3.44 min, (pos) [M+H]/z Calc'd 415.1, found 415.2.

[0442] The starting material was prepared as follows:

[0443]3-Iodo-6-(3-methoxy4-methoxymethoxy-phenyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas prepared from the compound prepared in Example l(a), step (v) in asimilar manner to that described for Example 10, step (ii): R_(f) sm0.11, p 0.43 (ethyl acetate-hexane 3:7); ¹H NMR (300 MHz, CDCl₃) δ 7.71(s, 1H), 7.55 (m, 2H), 7.33 (m, 1H), 7.20 (m, 2H), 5.82 (s, 2H), 5.33(s, 2H), 4.02 (s, 3H), 3.64 (t, 2H), 3.59 (s, 3H), 0.95 (t, 2H), −0.03(s, 9H).

[0444]3-Styryl-6-(3-methoxy4-methoxymethoxy-phenyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas prepared in a similar manner to that described for Example 11, step(iii): R_(f) sm 0.41, p 0.35 (ethyl acetate-hexane 2:8); ¹H NMR (300MHz, CDCl₃) δ 8.12 (d, 1H), 7.73 (s, 1H), 7.62 (m, 2H), 7.51 (m, 2h),7.46 (m, 2H), 7.38 (m, 1H), 7.30 (m, 4H), 5.85 (s, 2H), 5.38 (s, 2H),4.03 (s, 3H), 3.70 (t, 2H), 3.62 (s, 3H), 0.98 (t, 2H), −0.02 (s, 9H).

[0445]3-Carboxaldehyde-6-(3-methoxy-4-methoxymethoxy-phenyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas prepared in a similar manner to that described for Example 33(a),step (i): ¹H NMR (300 MHz, CDCl₃) δ 10.33 (s, 1H), 8.34 (d, 1H), 7.82(s, 1H), 7.65 (d, 1H), 7.25 (m, 3H), 5.90 (s, 2H), 5.36 (s, 2H), 4.02(s; 3H), 3.67 (t, 2H), 3.51 (s, 3H), 0.98 (t, 2H), -0.02 (s, 9H).

[0446]3-(4-Nitrostyryl)-6-(3-methoxy4-methoxymethoxy-phenyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas prepared in a similar manner to that described for Example 33(a),step (ii) except that 4-nitrobenzyltriphenylphosphonium bromide andlithium hexamethyldisilazide were used instead of2-picolyltriphenylphosphonium chloride-potassium hydride: LCMS (100%area) Rt=6.89 min, (pos) [M+H]/z Calc'd 562.4, found 562.4.

[0447]3-(4-Nitrostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole wasprepared in a similar manner to that described for Example 11: FTIR(thin film) 3335, 3178, 2954, 1592, 1512, 1338, 1257, 1136, 1257, 1136,987 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, 2H, J=8.8 Hz), 8.02 (d, 1H,J=8.5 Hz), 7.70 (d, 2H, J=8.8 Hz), 7.58 (m, 3H), 7.45 (dd, 1H, J=1.3,8.5 Hz), 7.20 (m, 4H), 7.26 (s, 2H), 3.95 (s, 3H), 3.53 (s, 3H); LCMS(100% area) Rt=5.13 min, (pos) [M+H]/z Calc'd 432.1, found 432.1.

[0448]3-(4-aminostyryl)-6-(3-methoxy4-methoxymethoxy-phenyl)-1H-indazole wasprepared in a similar manner to that described for Example 11, step(iv): R_(f) sm 0.39, p 0.26 (ethyl acetate-hexane 6:4); FTIR (thin film)3366, 3210, 2954, 1608, 1517, 1465, 1412, 1259, 1157, 1077,989,912cm⁻¹;¹H NMR(300 MHz, CDCl₃)δ8.11 (d, 1H), 7.63 (s, 1H), 7.50-7.15 (m, 8H),6.71 (d, 2H), 5.36 (s, 2H), 3.97 (s, 3H), 3.61 (s, 3H); LCMS (100% area)Rt=4.40 min, (pos) [M+H]/z Calc'd 402.2, found 402.2.

[0449]3-(⁴-aminostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (90mg, 0.224 mmol) was dissolved in dichloromethane (2 mL) and was treatedwith Boc-glycine (196 mg, 1.12 mmol, 5 equiv), DMAP (82 mg, 3 equiv) andHATU (426 mg, 5 equiv). The mixture was allowed to stir for 30 min. Themixture was partitioned between ethyl acetate and water. The organicmaterial was concentrated, taken up in methanol (5 mL) and was treatedwith potassium carbonate (100 mg). The mixture was heated to 50° C. for3 d. The resulting mix was again partitioned between ethyl acetate andwater. The organic material was concentrated, and purified by silica(109 mg, 66%): R_(f) sm 0.32, p 0.46 (ethyl acetate-hexane 6:4); ¹H NMR(300 MHz, CDCl₃) δ 8.18 (bs, 1H), 8.03 (d, 1H, J=8.1 Hz), 7.56 (m, 5H),7.40 (m, 3H), 7.20 (m, 3H), 5.29 (s, 2H), 5.20 (bs, 1H), 3.98 (s, 3H),3.96 (d, 2H), 3.54 (s, 3H), 1.48 (s, 9H).

Example 27(a): 6-phenyl-3-E-styryl-1H-indazole

[0450]

[0451] 6-phenyl-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole (345 mg, 0.81 mmol) was treated with a solution of TBAF (16 mlof a 1 M solution in THF, 16 mmol), and ethylene diamine (0.53 ml, 8.1mmol), and heated at 70° C. for 2 h. The solution was then poured intobrine (200 ml), and extracted with ethyl acetate (3×30 ml). The organiclayer was dried over MgSO₄, and concentrated under reduced pressure.Purification by silica gel chromatography gave6-phenyl-3-E-styryl-1H-indazole as a white solid (80 mg, 34%): ¹H NMR(300 MHz, CDCl₃) δ 8.10 (d, 1H, J=8.5 Hz); HRMS (FAB) [M+H]/z Calc'd297.1392, found 297.1393. Anal. Calc'd, C (85.10), H (5.44), N (9.45).Found: C (85.10), H (5.46), N (9.43).

[0452] The starting material was prepared as follows:

[0453] A solution of 476 mg (1.0 mmol) of6-iodo-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H- indazole, fromExample 14 step (i), in dioxane (3 ml, degassed by sonication andbubbling argon), Pd(PPh₃)₄ (23 mg, 0.05 mmol), phenylboronic acid (302mg, 2.5 mmol), and Na₂CO₃ (1.25 ml of a 2M aqueous solution, degassed asabove) was heated at 90° C. for 2 h. The solution was then diluted withethyl acetate (100 ml) and washed with brine (2×20 ml). The organiclayer was dried over MgSO₄, and concentrated under reduced pressure.Purification by silica gel chromatography gave of6-phenyl-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H- indazole asa brown oil (345 mg, 81%). ¹H NMR (300 MHz, CDCl₃) δ 8.09 (dd, 1H,J=8.5, 0.7 Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=7.0 Hz), 7.64-7.58 (m, 2H),7.56-7.51 (m, 2H), 7.50-7.45 (m, 2H), 7.45-7.36 (m, 4H), 7.34-7.27 (m,1H), 5.80 (s, 2H), 3.73 (t, 2H, J=8.3 Hz), 1.12 (t, 2H, J=8.3 Hz).

Example 27(b): 6-(3-methoxyphenyl)-3-E-styryl-1H-indazole

[0454]

[0455] Example 27 (b) was prepared in a similar manner to that describedfor Example 27(a), except that 3-methoxyphenylboronic acid was usedinstead of phenylboronic acid in step (i). ¹H NMR (300 MHz, MeOH-d4) δ8.16 (d, 1H, J=8.4 Hz), 7.70 (s, 1H), 7.67-7.61 (m, 2H), 7.60-7.43 (m,3H), 7.43-7.33 (m, 3H), 7.32-7.21 (m, 3H), 6.99-6.92 (m, 1H), 3.88 (s,3H). HRMS (FAB) [M+Na]/z Calc'd 349.1317, found 349.1342. Analyzed with0.1 H₂O Calc'd, C (80.50), H (5.59), N (8.55). Found: C (80.44), H(5.49), N (8.55).

Example 27(c): 6-(4-methoxyphenyl)-3-E-styryl-1H-indazole

[0456]

[0457] Example 27 (b) was prepared in a similar manner to that describedfor Example 27(a), except that 4-methoxyphenylboronic acid was usedinstead of phenylboronic acid in step (i). ¹H NMR (300 MHz, DMSO-d₆) δ13.20 (s, 1H), 8.23 (d, 1H, J=8.4 Hz), 7.76-7.64 (m, 5H), 7.54 (s, 1H),7.50-7.37 (m, 3H), 7.33-7.25 (m, 1H), 7.07 (d, 2H, J=8.8 Hz), 3.82 (s,3H) HRMS (FAB) [M+H]/z Calc'd 327.1497, found 327.1502. Anal. Calc'd, C(80.96), H (5.56), N (8.58). Found: C (80.71), H (5.42), N (8.47).

Example 27(d): 6-naphth-1-yl-3-E-styryl-1H-indazole

[0458]

[0459] Example 27 (d) was prepared in a similar manner to that describedfor Example 27(a), except that 1-naphthaleneboronic acid was usedinstead of phenylboronic acid in step (i) ¹H NMR (300 MHz, DMSO-d₆) δ10.11 (s, 1H), 8.45 (d, 1H. J=8.41), 7.97-7.87 (m, 3H), 7.66-7.37 (m,13H), 7.35-7.28 (m, 1H). HRMS (FAB) [M+Na]/z Calc'd 369.1368, found369.1359. Anal. Calc'd C (86.68), H (5.32), N (8.19). Found: C (86.52),H (5.32), N (8.19).

Example 27(e) 6-pyridin-3-yl-3-E-styryl-1H-indazole

[0460]

[0461] Example 27 (e) was prepared in a similar manner to that describedfor Example 27(a), except that 3-pyridineboronic acid was used insteadof phenylboronic acid in step (i). ¹H NMR (300 MHz, MeOH-d₄) δ 8.97 (s,1H), 8.63 (d, 1H, J=4.8 Hz), 8.30 (d, 1H, H=8.5 Hz), 8.27 (d, 1H, J=8.1Hz), 7.86 (s, 1H), 7.72 (d, 2H, J=7.5 Hz), 7.69-7.56 (m, 4H), 7.54-7.42(m, 2H), 7.40-7.32 (m, 1H). HRMS (FAB) [M+H]/z Calc'd 298.1344, found298.1356. Analyzed with 0.25 H₂O Calc'd, C (79.58), H (5.18), N (13.92).Found: C (79.53), H (5.16), N (13.80).

Example 27(f) 6-pyridin-4-yl-3-E-stryl-1H-indazole

[0462]

[0463] Example 27(f) was prepared in a similar manner to that describedfor Example 27(a), except that 4-pyridineboronic acid was used insteadof phenylboronic acid in step (i). ¹H NMR (300 MHz, MeOH-d4) δ 8.69 (bs,2H), 8.30 (d, 1H, J=8.5 Hz), 7.96 (s, 1H), 7.87 (d, 2H, H=5.6 Hz),7.75-7.68 (m, 3H), 7.68-7.50 (m, 2H), 7.50-7.42 (m, 2H), 7.40-7.31 (m,1H). HRMS (FAB) [M+H]/z Calc'd 298.1344, found 298.1357. Analyzed with0.3 H₂O Calc'd, C (79.34), H (5.19), N (13.88). Found: C (79.14), H(5.08), N (13.84).

Example 27(g): 6-indol-4-yl-3-E-styryl-1H-indazole

[0464]

[0465] Example 27(g) was prepared in a similar manner to that describedfor Example 27(a), except that 4-indoleboronic acid was used instead ofphenylboronic acid in step (i). ¹H NMR (300 MHz, MeOH-d4) δ 8.25 (d, 1H,J=8.5 Hz), 7.85 (s, 1H), 7.75-7.67 (m, 3H), 7.67-7.52 (m, 2H), 7.52-7.42(m, 3H), 7.39-7.22 (m, 4H), 6.72 (d, 1H, J=3.2 Hz). HRMS (FAB) [M+H]/zCalc'd 336.1501, found 336.1506. Analyzed with 0.3 H₂O Calc'd, C(78.97), H (5.36), N (12.01). Found: C (78.95), H (5.20), N (12.03).

Example 27(h): 6-[3-ethoxy-4-hydroxyphenyl]-3-E-styryl-1H-indazole

[0466]

[0467] Example 27(h) was prepared in a similar manner to that describedfor Example 27(a), except that3-ethoxy4-(2-trimethylsilanyl-ethoxymethoxy)benzene boronic acid wasused instead of phenylboronic acid in step (i). ¹H NMR (300 MHz, CDCl₃)δ 8.10 (d, 1H, J=8.7 Hz), 7.74 (s, 1H), 7.74-7.16 (m, 10H), 7.07 (d, 1H,J=8.15 Hz), 4.27 (q, 2H, J=14.0 Hz), 1.54 (t, 3H, J=14.0 Hz). HRMS (FAB)[M+H]/z Calc'd 357.1603, found 357.1611. Analyzed with 0.2 H₂O, Calc'd,C (76.73), H (5.71), N (7.78). Found: C (76.72), H (5.91), N (7.63).

[0468] Starting material was prepared as follows:

[0469] 4-Bromo-2-ethoxy-phenol (Smith et al., Soc. Pl., 1877-78 (1992))was converted to 3-ethoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-benzeneboronic acid in a manner similar to that described for Example 24(a)steps (vi)-(vii). ¹H NMR (300 MHz, CDCl₃) 6 7.82 (d, 1H, J=8.0 Hz), 7.72(s, 1H), 7.31 (d, 1H, J=8.1 Hz), 5.37 (s, 2H), 4.29 (q, 2H, J=14.0 Hz),3.87 (t, 2H, J=16.8 Hz), 1.54 (t, 2H, J=14.0 Hz), 0.99 (t, 2H, J=16.8Hz), 0.03 (s, 9H).

Example 27(i):6-[3-(2-hydroxyethoxy)-4-hydroxyphenyl]-3-E-styryl-1H-indazole

[0470]

[0471] Example 27(i) was prepared in a similar manner to that describedfor Example 27(a), except that³-[²-(trimethylsilanyl-ethoxymethoxy)-ethoxy]4-(2-trimethylsilanyl-ethoxymethoxy)-benzeneboronic acid, prepared from 2-(2-hydroxy-ethoxy)-phenol (Yamaguchi etal., Bull. Chem. Soc. Jpn., 61, 2047-54 (1988)) in a similar manner tothat described in Example 24(c) steps (i)-(iii) and was used instead ofphenylboronic acid in step (i). ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (d, 1H,J=8.7 Hz), 7.73-7.17 (m, 11 H), 6.92 (d, 1H, J=8.2 Hz), 4.13 (t, 2H,J=9.7 Hz), 3.8 (t, 2H, J=9.7 Hz). HRMS (FAB) [M+H]/z Calc'd 373.1552,found 373.1563. Analyzed with 0.05 trifluoroacetic acid, Calc'd, C(73.37), H (5.35), N (7.41). Found: C (73.11), H (5.33), N (7.39).

Example 27(i): 6-(3,4-dimethoxyphenyl)-3-E-styryl-1H-indazole

[0472]

[0473] Example 27 (j) was prepared in a similar manner to that describedfor Example ²7(a), except that 3,4-dimethoxyphenylboronic acid was usedinstead of phenylboronic acid in step (i). ¹H NMR (300 MHz, DMSO-d₆) δ8.01 (d, 1H, J=8.1 Hz), 7.51-7.05 (m, 11H), 6.86 (d, 1H, J=8.0 Hz) 3.58(s, 3H), 3.65 (s, 3H). HRMS (FAB) [M+H]/z Calc'd 357.1598, found357.1508. Analyzed with 0.2 H₂O, Calc'd, C (76.73), H (5.71), N (7.78).Found: C (76.45), H (5.70), N (7.68).

Example 27(k): 6-(2-methoxypyridin-5-yl)-3-E-styryl-1H-indazole

[0474]

[0475]6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazolewas converted to 6-(2-methoxypyridin-5-yl)-3-E-styryl-1H-indazole in asimilar manner to that described for Example 27(a). ¹H NMR (300 MHz,CDCl₃) □8.53 (d, 1H, J=2.1 Hz), 8.15 (d, 1H, J=9.2 Hz), 7.97 (dd, 1H,J=2.6, 8.6 Hz), 7.79 (s, 1H), 7.74-7.34 (m, 8H), 6.94 (d, 1H, J=8.6 Hz).HRMS (FAB) [M+H]/z Calc'd 328.1450, found 328.1462. Anal. Calc'd,.C(77.04), H (5.23), N (12.83). Found: C (77.00), H (5.28), N (12.65).

[0476] The starting material was prepared as follows:

[0477] A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol),hexamethylditin (1.15 g, 6.10 mmol), and Pd( PPh₃)₄ (0.28 g, 0.24 mmol)in degassed dioxane (10 ml ) was refluxed under for 16 h.6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(2.90 g, 6.10 mmol) was added to above mixture, followed by Pd( PPh₃)₄(0.35 g 0.31 mmol ). The reaction mixture was refluxed for 16 h. Themixture was then diluted with ethyl acetate (150 ml), and washed withbrine (30 ml). The organics were dried over MgSO₄, then concentratedunder reduced pressure. Purification by silica gel chromatography gave6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas a yellow solid (1.12 g, 40%). ¹H NMR (300 MHz, CDCl₃) δ 8.51 (d, 1H,J=2.5 Hz), 8.50 (d, 1H, J=9.1 Hz), 7.93 (dd, 1H, J=2.5, 8.6 Hz), 7.69(s, 1H), 7.69-7.28 (m, 8H), 6.89 (d, 1H, J=8.6 Hz), 5.83 (s, 2H), 4.03(s, 3H), 3.64 (t, 2H, J=8.3 Hz), 0.93 (t, 2H, J=8.3 Hz), -0.03 (s, 9H).

Example 28(a) 6-(3-hydroxyphenyl)-3-E-styryl-1H-indazole

[0478]

[0479] A solution of 100 mg (0.3 mmol)6-(3-methoxyphenyl)-3-E-styryl-1H-indazole, from Example 27(b), wascooled to −78° C. and treated with BBr₃ (1.8 ml of a 1M solution inCH₂Cl₂, 1.8 mmol). The resulting solution was held at −78° C. for 15min, then warmed to 0° C., and held 3 h. A solution of saturated aqueoussodium bicarbonate was then added (10 ml), followed by ethyl acetate (50ml). The organic layer was washed with brine (20 ml), then concentratedunder reduced pressure. Purification by silica gel chromatography gave6-(3-hydroxyphenyl)-3-E-styryl-1H-indazole as a white solid (55 mg,59%). ¹H NMR (300 MHz, MeOH-d4) δ 8.16 (d, 1H, J=8.5 Hz), 7.71-7.62 (m,3H), 7.61-7.44 (m, 3H), 7.43-7.35 (m, 2H), 7.33-7.25 (m, 2H), 7.20-7.10(m, 2H), 6.85-6.79 (m, 1H); 6 13.14 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1H,J=8.4 Hz), 7.73 (d, 2H, J=7.3), 7.64-7.52 (m, 5H), 7.47-7.37 (m, 3H),7.33-7.25 (m, 1H), 6.89 (d, 2H, J=8.6 Hz). cl Example 28(b):6-(4-hydroxyphenyl)-3-E-styryl-1H-indazole

[0480] 6-(4-methoxyphenyl)-3-E-styryl-1H-indazole, from Example 27(c),was converted to 6-(4-hydroxyphenyl)-3-E-styryl-1H-indazole in a similarmanner to that described for Example 28(a). ¹H NMR (300 MHz, DMSO-d₆) δ13.14 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1H, J=8.4 Hz), 7.73 (d, 2H, J=7.3Hz), 7.64-7.52 (m, 5H), 7.47-7.37 (m, 3H), 7.33-7.25 (m, 1H), 6.89 (d,2H, J=8.6 Hz). HRMS (FAB) [M+Na]/z Calc'd 313.1341, found 313.1347.Analyzed with 0.5 H₂O Calc'd, C (78.48), H (5.33), N (8.72). Found: C(78.35), H (5.26), N (8.49).

Example 28(c): 6-(2-hydroxypyridin-5-yl)-3-E-styryl-1H-indazole

[0481]

[0482] 6-(2-Methoxypyridin-5-yl)-3-E-styryl-1H-indazole indazole, fromExample 27(k), was converted to6-(2-hydroxypyridin-5-yl)-3-E-styryl-1H-indazole in a similar manner tothat described for Example 28(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.22 (d,1H, J=8.4 Hz), 7.96 (dd, 1H, J=2.6, 9.65 Hz), 7.81 (d, 1H, J=2.0 Hz) ,7.74-7.30 (m, 9H), 6.50 (d, 1H, J=9.4 Hz). HRMS (FAB) [M+H]/z Calc'd314.1293, found 314.1280. Analyzed with 0.1 trifluoroacetic acid,Calc'd, C (72.69), H (4.86), N (12.59). Found: C (72.77), H (4.81), N(12.65).

Example 28(d): 6-(3,4-dihydroxyphenyl)-3-E-styryl-1H-indazole

[0483]

[0484] 6-(3,4-Dimethoxyphenyl)-3-E-styryl-1H-indazole, from Example27(j), was converted 6-(3,4-dihydroxyphenyl)-3-E-styryl-1H-indazole in asimilar manner to that described for Example 28(a). ¹H NMR (300 MHz,DMSO-d₆) δ 9.09 (br s, 1H), 9.07 (br s, 1H), 8.20 (d, 1H, J=8.5), 7.73(d, 2H, J=7.5 Hz), 7.56 (d, 2H, J=10.1 Hz), 7.53 (s, 1H), 7.43-7.29 (m,4H), 7.11 (s, 1H), 7.04 (d, 1H, J=8.2 Hz), 6.86 (d, 1H, J=8.2 Hz). HRMS(FAB) [M+H]/z Calc'd 329.1290, found 329.1274. Analyzed with 1.0 H₂O,Calc'd, C (66.79), H (4.73), N (7.15). Found: C (66.54), H (4.56), N(7.36).

Example 29(a):6-pyrid4-yl-3-E-[2-(2,6-dichlorophenyl)ethenyl]-1H-indazole

[0485]

[0486]6-Pyrid-4-yl-3-E-[2-(2,6-dichlorophenyl)ethenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazolewas converted to6-pyrid-4-yl-3-E-[2-(2,6-dichlorophenyl)ethenyl]-1H-indazole in asimilar manner to that described for Example 27(a). ¹H NMR (300 MHz,CDCl₃) δ 13.55 (s, 1H), 8.68 (dd, 2H, J=4.6, 1.6 Hz), 8.21 (d, 1H, J=8.5Hz), 7.96 (s, 1H), 7.81 (dd, 2H, J=4.5, 1.6 Hz), 7.66 (dd, 1H, J1=8.5,1.4 Hz), 7.58 (d, 2H, J=8.0 Hz), 7.51 (s, 2H), 7.39-7.32 (m, 1H). MS(FAB) [M+H]/z Calc'd 366, found 366. Analyzed with 0.7 H₂O Calc'd, C(63.40), H (3.83), N (11.09). Found: C (63.63), H (3.75), N (10.83).

[0487] The starting material was prepared as follows:

[0488] 2,6-Dichlorobenzyl bromide (1.20 g, 5 mmol) was mixed withtriethyl phosphite (1.66 g, 10 mmol) and heated at 150° C. for 2 h. Theresulting mixture was then distilled at 160 ° C under reduced pressure(10 mm Hg) to remove the excess triethyl phosphite.(2,6-Dichloro-benzyl)-phosphonic acid diethyl ester was obtained as acolorless liquid (1.⁴6 g, 100%). ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.28 (m,2H), 7.15-7.07 (m, 1H), 4.144.02 (m, 4H), 3.60 (d, 2H, J=22.4 Hz), 1.27(t, 6H, J=7.0 Hz).

[0489] Ozone gas was bubbled through a solution of6-pyrid4-yl-3-E-styryl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(2.13 g, 5.0 mmol) in TIF (25 ml) and MeOH (25 ml) at −78° C. for 15min. Argon was then bubbled through the solution for 10 min at −78° C.for 10 min, then dimethyl sulfide (1.46 ml, 20 mmol) was added. Thesolution was allowed to warm to rt, and held for 2 h. The solution waspoured into brine (300 ml), then extracted with ethyl acetate (3×100ml). The organics were dried over MgSO₄, then evaporated under reducedpressure. Purification by silica gel chromatography gave6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydeas a white solid (2.2 g, 75%). ¹H NMR (300 MHz, CDCl₃) δ 10.39 (s, 1H),8.75 (d, 2H, J=1.6 Hz), 8.45 (d, 1H, J=2.8 Hz), 7.91 (s, 1H), 7.75-7.66(m, 3H), 5.90 (s, 2H), 3.63 (t, 2H, J=2.7 Hz), 0.93 (t, 2H, J=2.8 Hz),0.00 (s, 9H).

[0490] A solution of (2,6-dichlorobenzyl)phosphinic acid diethyl ester(582 mg, 2.0 mmol) in DMF (15 ml) was cooled to ⁰° C. and treated withNaH (160 mg of 60% in mineral oil, 4.0 mmol). The resulting solution washeld at 0° C. for 30 min, then treated with6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde(353 mg, 1.0 mmol). The resulting solution was allowed to warm to rtover 1 h, then held at rt 2h. The solution was poured into brine (250ml), then extracted with ethyl acetate (3×80 ml). The organics weredried over MgSO₄, then concentrated under reduced pressure. Purificationby silica gel chromatography gave6-pyrid-4-yl-3-E-[2-(2,6-dichlorophenyl)ethenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas a yellow oil (330 mg, 67 %). ¹H NMR (300 MHz, CDCl₃) δ 7.72 (dd, 2H,J=4.6, 1.5 Hz), 8.16 (d, 1H, J=8.5 Hz), 7.84 (s, 1H), 7.62 (ss, 2H,J=4.5, 1.6 Hz), 7.60 (s, 2H), 7.56 (dd, 1H, J=8.5, 1.5 Hz), 7.39 (d, 1H,J=8.1 Hz), 7.18-7.12 (m, 1H), 3.64 (t, 2H, J=8.3 Hz), 0.92 (t, 2H, J=8.3Hz), 0.00 (s, 9H).

Example 29(b): 6-pyrid-4-yl-3-E-[2-(3-methylphenyl)ethenyl]-1H-indazole

[0491]

[0492]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to the desired product in a similar manner to thatdescribed for Example 29(a). ¹H NMR (300 MHz, MeOH-d4) 8.88 (d, 1H,J=6.7 Hz), 8.41-8.35 (m, 3H), 8.16 (s, 1H), 7.80 (dd, 1H, J=8.6, 1.6Hz), 7.67-7.48 (m, 4H), 7.35 (t, 1H, J=7.6 Hz), 7.22-7.17 (m, 1H), 4.88(s, 3H). MS (FAB) [M+H]/z Calc'd 312, found 312. Analyzed with 0.2 H₂0,1.1 trifluoroacetic acid Calc'd, C (63.27), H (4.23), N (9.54). Found: C(63.08), H (4.18), N (9.80).

Example 29(c): 6-pyrid-4-yl-3-E-[2-(4-chlorophenyl)ethenyl]-1H-indazole

[0493]

[0494]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to the desred product in a similar manner to thatdescribed for Example 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H),8.67 (dd, 2H; J=4.6, 1.6 Hz), 8.33 (d, 1H, J=8.5 Hz), 7.92 (s, 1H), 7.81(dd, 2H, J=4.6, 1.6 Hz), 7.78 (d, 2H, J=8.5 Hz), 7.67-7.56 (m, 3H), 7.46(d, 2H, J=8.5 Hz). Analyzed with 0.15 H₂O, Calc'd, C (71.81), H (4.31),N (12.56). Found: C (71.85), H (4.26), N (12.48).

Example 29(d): 6-pyrid-4-yl-3-E-[2-(biphenyl-4-yl)ethenyl]-1H-indazole

[0495]

[0496]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(d) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 8.68 (d, 2H,J=4.6, 1.5 Hz), 8.35 (d, 1H, J=8.5 Hz), 7.93 (s, 1H), 7.87-7.79 (m, 4H),7.73 (d, 4H, J=8.1 Hz), 7.66-7.60 (m, 3H), 7.45 (m, 2H), 7.41-7.34 (m,1H). MS (FAB) [M+H]/z Calc'd 374, found 374. Analyzed with 0.20 H₂OCalc'd, C (82.82), H (5.19), N (11.15). Found: C (82.82), H (5.19), N(11.16).

Example 29(e): 6-pyrid-4-yl-3-E-[2-(3-methoxyphenyl)ethenyl]-1H-indazole

[0497]

[0498]6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(e) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.39 (s, 1H), 8.67 (d, 2H,J=5.3 Hz), 8.33 (d, 2H, J=8.5 Hz), 7.92 (s, 1H), 7.81 (dd, 2H, J=4.6,1.5 Hz), 7.65-7.54 (m, 3H), 7.35-7.28 (m, 3H), 3.83 (s, 3H). MS (FAB)[M+H]/z Calc'd 328, found 328. Analyzed with 0.20 H₂O Calc'd, C (76.20),H (5.30), N (12.70). Found: C (76.17), H (5.34), N (12.65).

Example 29(f): 6-pyrid-4-yl-3-E-[2-(pyrid-2-yl)ethenyl]-1H-indazole

[0499]

[0500]6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(f) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (dd, 2H, J=4.5, 1.6 Hz),8.62 (d, 1H, J=3.8 Hz), 8.33 (d, 1H, J=8.5 Hz), 7.99 (d, 1H, J=16.4 Hz),7.94 (s, 1H), 7.86-7.78 (m, 3H), 7.73-7.57 (m, 3H), 7.32-7.26 (m, 1H).Analyzed with 0.05 H₂O Calc'd, C (76.26), H (4.75), N (18.72). Found: C(76.22), H (4.79), N (18.76).

Example 29(g): 6-pyrid4-yl-3-E-[2-(3-fluorophenyl)ethenyl]-1H-indazole

[0501]

[0502]6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(g) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 8.68 (dd, 2H,J=4.5, 1.6 Hz), 8.34 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.81 (dd, 2H,J1=4.5, 1.6 Hz), 7.74-7.52 (m, 5H), 7.49-7.40 (m, 1H), 7.16-7.07 (m,1H). MS (FAB) [M+H]/z Calc'd 316, found 316. Anal. CaIc'd, C (76.17), H(4.48), N (13.33). Found: C (76.07), H (4.53), N (13.36).

Example 29(h): 6-pyrid-4-yl-3-E-[2-(2-fluorophenyl)ethenyl]-1H-indazole

[0503]

[0504]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(h) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.43 (s, 1H), 8.66 (dd, 2H,J=4.5, 1.6 Hz), 8.23 (d, 1H, J=8.2 Hz), 7.98-7.90 (m, 2H), 7.80 (dd, 2H,J=4.5, 1.7 Hz), 7.73-7.54 (m, 3H), 7.40-7.31 (m, 1H), 7.30-7.21 (m, 2H).MS (FAB) [M+H]/z Calc'd 316, found 316. Anal. Calc'd, C (76.17), H(4.48), N (13.33). Found: C (76.12), H (4.51), N (13.29).

Example 29(i): 6-pyrid-4-yl-3-E-[2-(3-chlorophenyl)ethenyl]-1H-indazole

[0505]

[0506]6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(i) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 8.68 (dd, 2H,J=4.5, 1.6 Hz), 8.35 (d, 1H, J=8.1 Hz), 7.92 (s, 1H), 7.86 (s, 1H), 7.82(dd, 2H, J=4.5, 1.7 Hz), 7.74-7.51 (m, 4H), 7.43 (t, 1H, J=7.8 Hz),7.37-7.21 (m, 1H). MS (FAB) [M+H]/z Calc'd 332, found 332. Anal. Calc'd,C (72.40), H (4.25), N (12.67). Found: C (72.52), H (4.28), N (12.57).

Example 29(j):6-pyrid-4-yl-3-E-[2-(2-methylthiazol-4-yl)ethenyl]-1H-indazole

[0507]

[0508]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1Hindazole-3-carbaldehydewas converted to Example 290) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.38 (s, 1H), 8.67 (dd, 2H,J=4.5, 1.6 Hz), 8.25 (d, 1H, J=8.5 Hz), 7.92 (s, 1H), 7.81 (dd, 2H,J=4.5, 1.6 Hz), 7.70-7.50 (m, 4H), 2.72 (s, 3H). MS (FAB) [M+H]/z Calc'd319, found 319. Analyzed with 0.15 trifluoroacetic acid, Calc'd, C(65.51), H (4.25), N (16.70). Found: C (65.56), H (4.37), N 16.53).

Example 29(k): 6-pyrid-4-yl-3-E-[2-(naphthalen-2-yl)ethenyl]-1H-indazole

[0509]

[0510]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1Hindazole-3-carbaldehydewas converted to Example 29(k) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 8.68 (dd, 2H,J=4.6, 1.4 Hz), 8.39 (d, 1H, J=8.5 Hz), 8.17 (s, 1H), 8.09-7.89 (m, 8H),7.83 (dd, 2H, J=4.6, 1.6 Hz), 7.74 (s, 2H), 7.65 (dd, 1H, J=8.5, 1.4Hz), 7.60-7.46 (m, 4H). MS (FAB) [M+H]/z Calc'd 348, found 348. Analyzedwith 1.05 trifluoroacetic acid, Calc'd, C (67.10), H (3.89), N (9.00).Found: C (67.20), H (3.93), N (9.05).

Example 29(l):6-pyrid4-yl-3-E-[2-(2,3-difluorophenyl)ethenyl]-1H-indazole

[0511]

[0512]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(1) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, CDCl₃ +MeOH-d4) δ 8.68 (d, 2H, J=5.6Hz,), 8.02 (d, 1H, J=8.5 Hz), 7.70 (s, 1H), 7.58 (dd, 2H, J=4.8, 1.5Hz), 7.57-7.39 (m, 3H), 7.38-7.31 (m, 1H), 7.06-6.96 (m, 2H). MS (FAB)[M+H]/z Calc'd 334, found 334. Analyzed with 0.80 H₂O, Calc'd, C(69.08), H (4.23), N (12.08). Found: C (68.77), H (3.93), N (11.85).

Example 29(m):6-pyrid-4-yl-3-E-[2-(3,5-difluorophenyl)ethenyl]-1H-indazole

[0513]

[0514]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(m) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, MeOH-d4) δ 8.69 (d, 2H, J=6.3 Hz), 8.34(d, 1H, J=8.5 Hz), 7.97 (s, 1H), 7.97 (d, 2H, J=6.3 Hz), 7.71 (d, 1H,J=10.0 Hz), 7.62 (s 1H), 7.60 (s, 1H), 7.36 (d, 1H, J=11.11), 6.95-6.89(m, 1H). MS (ES) [M+H]/z Calc'd 334, found 334. Anal. Calc'd, C (72.06),H (3.93), N (12.61). Found: C (72.20), H (4.01), N (12.58).

Example 29(n): 6-pyrid-4-yl-3-E-[2-(biphenyl-3-yl)ethenyl]-1H-indazole

[0515]

[0516]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(n) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (d, 2H, J=6.1 Hz ), 8.39(d, 1H, J=8.5 ), 8.04 (s, 1H), 7.92 (s, 1H), 7.82 (d, 2H, J=6.2 Hz),7.79-7.37 (m, 11 H). MS (ES) [M+H]/z Calc'd 374, found 374. Anal.Calc'd, C (83.62), H (5.13), N (11.25). Found: C (83.47), H (5.08), N(11.32).

Example 29(o):6-pyrid-4-yl-3-E-[2-(2,6-difluorophenyl)ethenyl]-1H-indazole

[0517]

[0518]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(o) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, MeOH-d4) δ 8.69 (d, 2H, J=6.3 Hz), 8.21(d, 1H, J=8.6 Hz), 7.97 (s, 1H), 7.88 (d, 2H, J=6.3 Hz), 7.83 (d, 1H,J=17.1 Hz), 7.71 (1H, J=8.6 Hz), 7.65 ( d, 1H, J=17.1 Hz ), 7.40-7.35(m, 1H), 7.13-7.08 (m, 2H). MS (ES) [M+H]/z Calc'd 334, found 334.Analyzed with 0.1 H₂O, Calc'd, C (71.67), H (3.97), N (12.54). Found: C(71.37), H (3.90), N (12.31).

Example 29(p):6-pyrid-4-yl-3-E-[2-(3-trfluoromethoxyphenyl)ethenyl]-1H-indazole

[0519]

[0520]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(p) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (d, 2H, J=6.4 Hz), 8.43(d, 1H, J=8.5 Hz), 8.19 (d, 2H, J=6.4 Hz), 8.07 (s, 1H), 7.81-7.27 (m,5H), 7.78 (s, 1H). MS (ES) [M+H]/z Calc'd 382, found 382. Analyzed with1.0 trifluoroacetic acid, Calc'd, C (55.76), H (3.05), N (8.48). Found:C (55.84), H (3.09), N (8.45).

Example 29(q):6-pyrid4-yl-3-E-[2-(benzimidazol-2-yl)ethenyl]-1H-indazole

[0521]

[0522]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(q) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (d, 2H, J=6.1 Hz), 8.25(d, 1H, J=8.5 Hz), 8.03 (d, 1H, J=16.7 Hz), 7.97 (s, 1H ), 7.84 (d, 2H,J=6.2), 7.72 (d, 1H, J=8.5 Hz), 7.60-7.57 (m, 2H), 7.53 (d, 1H, J=16.7Hz), 7.22-7.19 (m, 2H). MS (ES) [M+H]/z Calc'd 338, f338. Analyzed with2.0 trifluoroacetic acid, 0.2 H₂O, Calc'd, C (52.77), H (3.08), N(12.31). Found: C (52.59), H (3.17), N (12.18).

Example 29(r):6-pyrid-4-yl-3-E-[2-(3,4-methylenedioxyphenyl)ethenyl]-1H-indazole

[0523]

[0524]6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29r in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (d, 2H, J=6.1 Hz), 8.30(d, 1H, J=8.5 Hz), 7.89 (s,1H), 7.81 (d, 2H, J=6.1 Hz), 7.61 (d, 1H,J=9.9 Hz), 7.46-7.42 (m, 3H), 7.18 (d, 1H, J=9.6 Hz), 6.95 (d, 1H, 8.0Hz), 6.05 (s, 2H). MS (ES) [M+H]/z Calc'd 342, found 342. Anal. Calc'd,C (73.89), H (4.43), N (12.31). Found: C (73.74), H (4.52), N (12.40).

Example 29(s):6-pyrid-4-yl-3-E-[2-(2,5-difluorophenyl)ethenyl]-1H-indazole

[0525]

[0526]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(s) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, MeOH-d4) δ 8.53 (d, 2H, J=6.0 Hz), 8.03(d, 1H, J=8.5 Hz), 7.60 (d, 2H, J=6.2 Hz), 7.56-7.35 (m, 3H), 7.34-7.26(m, 1H), 7.03-6.93 (m, 1H), 6.90-6.81 (m, 1H). MS (ES) [M+H]/z Calc'd334, found 334. Analyzed with 0.30 H₂O, Calc'd, C (70.91), H (4.05), N(12.37). Found: C (70.97), H (4.17), N (12.37).

Example 29(t): 6-pyrid-4-yl-3-E-[2-(1H-pyrrol-2-yl)ethenyl]-1H-indazole

[0527]

[0528] 6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazole-3-carbaldehyde was converted to Example 29(t) in a similarmanner to that described for Example 29(a). ¹H NMR (300 MHz, MeOH-d4) δ8.60 (d, 2H, J=6.3 Hz), 8.13 (d, 1H, J=8.5 Hz), 7.86 (s<, 1H), 7.79 (d,2H, J=6.2 Hz), 7.57 (dd, 1H, J1=8.5 Hz, J2=1.5 Hz), 7.40 (d, 1H, J=16.8Hz), 7.09 (d, 1H, J=16.7 Hz), 6.87-6.82 (m, 1H), 6.40-6.35 (m, 1H), 6.16(t, 1H, J=2.9 Hz). MS (ES) [M+H]/z Calc'd 287, found 287. Analyzed with0.5 ethyl acetate, 0.3 tetrahydrofuran, 0.1 hexanes, 0.1 ethylenediamine, Calc'd, C (72.07), H (6.21), N (16.05). Found: C (71.95), H(6.20), N (15.76).

[0529] The starting material was prepared as follows:

[0530] (i) A solution of 1H-pyrrole-2-carbaldehyde (9.5 g, 100 mmol) andTHF (500 ml) was cooled with an ice bath. Bu^(t)ONa (19.2 g, 200 mmol)was added and reaction mixture was stirred at 0° C. for 1 h. MtsCl (32.7g, 150 mmol) was then added. The reaction mixture was allowed to warm tort and held for 2 h at rt. The solution was then treated with saturatedaqueous NH4CI (100 ml) and the mixture was poured into brine (2 L). Themixture was extraced with EtOAc (3×300 ml). The combined organic layerwas dried over MgSO₄ and concentrated under reduced pressure. Theresulting oil was purified by silica gel chromatography to yield1-(2,4,6-trimethyl-benzenesulfonyl)-1H-pyrrole-2-carbaldehyde as a lightyellow oil (15.7 g, 57%). 1H NMR (CDCl₃) δ 9.50 (s, 1H), 7.79-7.74 (m,1H), 7.12 (dd, 1H, J=3.7, 1.8 Hz), 6.95 (s, 2H), 6.38 (t, 1H, J=3.4 Hz),2.50 (s, 6H), 2.30 (s, 3H).

[0531] (ii)1-(2,4,6-Trimethyl-benzenesulfonyl)-1H-pyrrole-2-carbaldehyde (2.77 g,10 mmol) in THF (100 ml) was treated with LiBH4 (0.44 g, 20 mmol) at rt.The resulting solution was held at rt for 1 h. MeOH (10 ml) was thenadded, and the resulting mixture mixture was poured into brine (600 ml),and extracted with EtOAc (3×200 ml). The combined organic layer wasdried over MgSO₄ and concentrated under reduced pressure. The resultingoil was then purified on silica gel column to yield[1-(2,4,6-Trimethyl-benzenesulfonyl)-1H-pyrrol-2-yl]-methanol as a lightbrown oil (2.43 g, 87%). ¹H NMR (CDCl₃) δ 7.17 (dd, 1H, J=3.3, 1.8 Hz),6.99 (s, 2H), 6.28-6.23 (m, 1H), 6.18 (t, 1H, J=3.3 Hz), 4.42 (s, 2H),2.50 (s, 6H), 2.30 (s, 3H).

[0532] (iii) A solution of[1-(2,4,6-Trimethyl-benzenesulfonyl)-1H-pyrrol-2-yl]-methanol (1.4 g,5.0 mmol) in CHCl₃ (25 ml) was cooled with an ice bath. SOCl₂ (1.1 ml,15 mmol) was added slowly. The solution was allowed to warm to rt, andheld an additional 45 min. The solution was then concentrated underreduced pressure.2-Chloromethyl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-pyrrole wasobtained as a brown solid (1.5 g, 100%). ¹H NMR (CDCl₃) δ 7.28 (dd, 1H,J=3.3, 1.7 Hz), 6.98 (s, 2H), 6.38-6.34 (m, 1H), 6.19 (t, 1H, J=3.4 Hz),4.58 (s, 2H), 2.50 (s, 6H), 2.30 (s, 3H).

Example 29(u):6-pyrid-4-yl-3-E-[2-(3-methylcarbamoylmethoxyphenyl)ethenyl]-1H-indazole

[0533]

[0534]6-Pyridin4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(u) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, MeOH-d4) δ 8.68 (d, 2H, J=5.9 Hz), 8.51(br s, 1H), 8.37 (d, 1H, J=8.5 Hz), 8.19 (s, 1H), 7.93 (s,1H), 7.87 (d,1H, J=7.7 Hz), 7.85 (d, 2H, J=6.1 Hz), 7.62 (d, 1H, J=8.1 Hz),7.65-7.63(m, 3H), 7.51 (t, 1H, J=7.6 Hz). MS (ES) [M+H]/z Calc'd 355,found 355. Analyzed with 0.4 trifluoroacetic acid, 0.50 H₂O, Calc'd, C(69.67), H (4.98), N (14.26). Found: C (69.78), H (5.18), N (14.08).

Example 30(a):6-[3-benzamidophenoxy]-3-E-[2-(thien-2-yl)ethenyl]-1H-indazole

[0535]

[0536] Example 30(a) was prepared in a manner similar to example 6(a)except that (E)-3-thiophen-2-yl-acryloyl chloride was used in place of3-(4-chlorophenyl)acryloyl chloride in step (i). ¹H NMR (DMSO-d₆) δ13.05 (s, 1H), 10.33 (s, 1H), 8.19 (d, 1H, J=8.8 Hz), 7.92 (d, 2H, J=6.9Hz), 7.70 (d, 1H, J=16.5 Hz), 7.65-7.49 (m, 6H), 7.40 (t, 1H, J=8.1 Hz),7.35 (s, 1H, with fine splitting), 7.20 (d, 1H, J=16.5 Hz),7.10 (m, 1H),7.04 (s, 1H), 6.98 (d, 1H, J=8.8 Hz), 6.86 (s, 1H, J=9.8 Hz). Anal. Calcfor C₂₆H₁₉N₃O₂S.0.6 H₂O: C, 69.65; H, 4.54; N, 9.37; S, 7.15. Found: C,69.77; H, 4.45; N, 9.52; S, 7.02.

Example 30(b)6-[3-(1-acetylpiperidin-4-ylcarboxamido)phenoxy]-3-E-[2-(4-chlorophenyl)ethenyl]-1H-indazole

[0537]

[0538] Example 30(b) was prepared in a similar manner to that describedfor 6(a) except that 1-acetyl-piperidine-4-carboxylic acid and HATU wasused in place of benzoyl chloride in step(ii). ¹H NMR (DMSO-d₆) (J=8.6Hz) δ 7.76, (d, J=8.6 Hz), 7.53 (d, J=6.2 Hz), 7.46 (d, J=8.4 Hz), 7.37(m, 3H), 7.01 (s, 1H, with fine splitting), 6.97 (d, J=8.8 Hz), 6.78 (d,J=7.7 Hz), 4.38 (m, 1H), 3.85 (m, 1H), 3.09-2.96 (m, 1H), 2.58 (m, 2H),1.99 (s, 3H), 1.77 (m, 2H), 1.55 (m, 1H), 1.37 (m, 1H). Anal. Calc forC₂₉H₂₇CIN₄0₃ 1.3 H₂0: C, 64.69; H, 5.54; N, 10.41. Found: C, 64.64; H,5.51; N, 10.23.

Example 30(c):6-[3-benzamidophenoxy]-3-E-[2-(fur-2-yl)ethenyl]-1H-indazole

[0539]

[0540] Example 30(c) was prepared in a manner similar to example 6(a)except that (E)-3-furan-2-yl-acryloyl chloride, prepared according toCollect, Czech. Chem. Comm., 52, 409-24 (1987), was used in place of3-(4-chlorophenyl)-acryloyl chloride in step (i). ¹H NMR (DMSO-d₆) δ13.00 (s, 1H), 10.32 (s, 1H), 8.14 (d, 1H, J=8.8 Hz), 7.91 (d, 2H, J=7.0Hz), 7.73 (s, 1H), 7.70-7.51 (m, 5H), 7.40 (t, 1H, J=8.4 Hz), 7.30 (AB,2H, J=16.7 Hz), 7.04 (s, 1H), 6.98 (d, 1H, J=8.7 Hz), 6.86 (d, 1H, J=8.0Hz), 6.65 (s, 1H,with fine splitting), 6.60 (s, 1H,with fine splitting).Anal. Calc for C₂6H₁₉N₃O_(2.)0.7 H₂O: C, 71.94; H, 4.74; N, 9.68. Found:C, 72.17; H, 4.83; N, 9.44.

Example 30(d): 6-[3-(indol-4-ylcarboxamido)phenoxy]-3-E-stryrylindazole

[0541]

[0542] Example 30(d) was prepared in a similar manner to that describedfor Example 30(a) using 3-(styryl-1H-indazol-6-yloxy)-phenylamine inplace of 3-(3-styryl-4,5-dihydro-1H-indazol-6-yloxy)phenylamine and1H-indole-4-carboxylic acid in place of benzoic acid in step (ii). ¹HNMR (DMSO-d₆) δ 12.99 (s, 1H), 11.33 (s, 1H), 10.24 (s, 1H), 8.22 (d,1H, J=8.7 Hz), 7.72-7.38 (m, 10H), 7.30 (d, 1H, J=7.1 Hz), 7.19 (m, 2H),7.04 (m, 3H), 6.82 (m, 2H). Anal. Calc for C₃₀H₂₂N₄0₂ 0.6 H₂O: C, 74.86;H, 4.86; N, 11.64. Found: C, 74.90; H, 5.01; N, 11.33.

Example 30(e):6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-stryrylindazole

[0543]

[0544] Example 30(e) was prepared in a similar manner to that describedfor Example 30(a) using ³-(styryl-1H-indazol-6-yloxy)-phenylamine inplace of 3-(3-styryl-4,5-dihydro-1H-indazol-6-yloxy)phenylamine and1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid in place of benzoic acidin step (ii).

Example 31(a):6-[3-benzanidophenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0545]

[0546] To a stirred solution of6-[3-benzamidophenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-4,5-dihydro-1H-indazole(492 mg, 1.13 mmol) in 15 mL of 1,4-dioxane was added 386 mg (1.7 mmol)2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The reaction mixturewas stirred for 30 min at room temperature, then poured into sat NaHCO₃solution and EtOAc. Layers were separated and the aqueous layer wasre-extracted with EtOAc. The combined organic layers were washedsequentially with sat NaHCO₃ solution and sat NaCl solution, dried overMgSO₄ and conc. under reduced pressure. The residue was flashchromatographed on silica gel eluting CH₂Cl₂/EtOAc: MeOH (1:1:0.1). Theoil obtained was triturated from EtOAc/hexanes to give the titlecompound as a tan solid (420 mg, 86%). ¹H NMR (DMSO-d₆) δ 13.12 (s, 1H),10.30 (s, 1H), 8.60 (d, 1H, J=3.8 Hz), 8.22 (d, 1H, J=8.8 Hz), 7.93 (m,3H), 7.82 (t, 1H, J=7.7 Hz), 7.68-7.49 (m, 7H), 7.40 ( t, 1H, J=8.1 Hz),7.27 (m, 1H), 7.08 (s, 1H), 7.03 (s,1H), 7.03 (d, 1H, J=8.7 Hz), 6.87(d, 1H, J=8.1 Hz, with fine splitting). Anal. Calc for C₂₇H₂oN₄0₂ 0.65EtOAc: C, 72.59; H, 5.19; N, 11.44. Found: C, 72.34; H, 5.11; N, 11.82.

[0547] The starting material was prepared as follows:

[0548] A solution of3-[3-(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone (4.00 g, 10.9nimol) in 20 mL of THF was added slowly to a −78° C. solution of LiHMDS(36 mL of 1.0M solution in THF). Fifteen minutes after addition wascomplete, (E)-3-pyridin-2-yl-acryloyl chloride hydrochloride was addedand stirring was continued at −78° C. for 30 min. The reaction wasquenched with sat. NH₄Cl solution and extracted with EtOAc (3×). Thecombined organic layers were washed with sat NaCl solution, dried overMgSO₄ and conc. under reduced pressure. The residue was flashchromatographed on silica gel eluting Hexanes/EtOAc (2: 1). Theappropriate fractions were concentrated under reduced pressure anddissolved in EtOH/HOAc (1:1, 8 ml). To this solution at 80° C. was addedhydrazine hydrate (3.4 ml, 70.0 mmol). After 15 min, all startingmaterial was gone and the reaction mixture was cautiously poured intosat. NaHCO₃ and extracted with EtOAc (2×). The combined organic layerswere washed with sat NaCI solution, dried over MgSO₄ and conc. underreduced pressure. The residue was flash chromatographed on silica geleluting CH₂Cl₂/MeOH (9:1) to give6-(3-aminophenoxy)-3-E-[2-(pyridin-2-yl)ethenyl]-4,5-dihydro-1H-indazole(676 mg, 19%). ¹H NMR (DMSO-d₆) δ 12.51 (s, 1H), 8.57 (d, 1H, J=3.8 Hz),7.78 (t, 1H, J=7.8 Hz), 7.51 (m, 2H), 7.25 (m, 1H), 7.05 (m, 2H), 6.35(d, 1H, J=7.9 Hz, with fine splitting), 6.32 (t, 1H, J=2.1 Hz), 6.23 (d,1H, J=7.9 Hz), 5.54 (s, 1H), 5.23 (s, 2H), 2.95 (t, 2H, J=8.2 Hz), 2.60(t, 2H, J=8.2 Hz); MS [m+H]/z Calc'd 331. Found: 331. Anal. Calc forC₂₀H₁₈N₄O.0.15 H₂O: C, 72.12; H, 5.54; N, 16.82. Found: C, 72.11; H,5.55; N, 16.61.

[0549] To a stirred solution of the dihydro aniline (350 mg, 1.06 mmol)and benzoic acid (776 mg, 6.36 mmol) in 15 mL of DMF, was added HATU(2.42 g, 6.36 mmol) and NEt₃ (1.8 ml, 12.71 mmol). The reaction mixturewas heated at 50° C. for 1.5 hr, cooled and poured into ice/sat NaCIsolution. The ppt was collected by vacuum filtration, washed with H₂Oand air dried. To this filter cake dissolved in 10 mL of MeOH/THF (1:1),was added K₂CO₃ (650 mg) and 1 mL of H₂O. After 1 hr, the reactionmixture was poured into sat NaCl solution and extracted with EtOAc (2×).The combined organic layers were washed with sat NaCl solution, driedover MgSO₄ and conc. under reduced pressure. The residue was flashchromatographed on silica gel eluting CH₂Cl₂/EtOAc/MeOH (1:1:0.1) togive6-[3-benzamidophenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-4,5-dihydro-1H-indazole(333 mg, 72%). ¹H NMR (DMSO-d₆) δ 12.58 (bs, 1H), 10.34 (s, 1H), 8.57(d, 1H, J=3.8 Hz), 7.95 (d, 2H, J=6.8 Hz), 7.81-7.70 (m, 2H), 7.63-7.50(m, 6H), 7.40 (t, 1H, J=8.1 Hz), 7.25 (m, 1H), 7.09 (d,1H, J=16.3 Hz),6.89 (d, 1H, J=8.0 Hz ), 5.64 (s, 1H), 2.99 (t, 2H, J=8.1 Hz), 2.66 (t,2H, J=8.1 Hz). Anal. Calc for C₂₇H₂₂N₄0₂ 0.1 CH₂Cl₂: C, 73.48; H, 5.05;N, 12.65. Found: C, 73.48; H, 5.05; N, 12.48.

Example 31(b):6-[3-((1,5-Dimethyl-1H-pyrazol-3-yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0550]

[0551] Example 31(b) was prepared in a similar manner to that describedfor Example 31(a) except that 1,5-dimethyl-1H-pyrazole-3 carboxylic acidwas used in place of benzoic acid in step (ii). ¹H NMR (DMSO-d₆) δ 13.13(s, 1H), 10.07 (s, 1H), 8.60 (d, 1H, J=4.3 Hz), 8.21 (d, 1H, J=8.7 Hz),7.93 (d, 1H, J=16.3 Hz), 7.82 (t, 1H, J=7.4 Hz), 7.69 (m, 3H), 7.56 (d,1H, J=16.3 Hz), 7.32 (m, 2H), 7.05 (s, 1H), 7.01 (d, 1H, J=8.7 Hz), 6.80(m, 1H), 6.52 (s, 1H), 3.81 (s, 3H) 2.29 (s, 3H). Anal. Calc forC₂₆H₂₂N₆O₂.0.1 CH₂Cl₂/0.1 hexanes: C, 68.58; H, 5.09; N, 17.97. Found:C, 68.26; H, 5.25; N, 17.61.

Example 31(c):6-[3-((5-methylsulfonylthien-2-yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0552]

[0553] Example 31(c) was prepared in a similar manner to that describedfor Example 31(a) except that 5-methanesulfonyl-thiophene-2-carboxylicacid was used in place of benzoic acid in step (ii). ¹H NMR (DMSO-d₆) δ13.17 (s, 1H), 10.58 (s, 1H), 8.61 (d, 1H, J=4.0 Hz), 8.24 (d, 1H, J=8.8Hz), 8.05 (d, 1H, J=4.1 Hz), 7.97-7.79 (m, 3H), 7.68 (d, 1H, J=7.8 Hz),7.60-7.48 (m, 3H), 7.43 (t, 1H, J=8.2 Hz), 7.28 (m, 1H), 7.10 (s,1H,with fine splitting), 7.00 (d, 1H, J=8.7 Hz), 6.92 (d, 1H, J=8.1 Hz,with fine splitting), 3.41 (s, 3H). Anal. Calc for C₂₆H₂₀N₄O₄.S₂ 0.4EtOAc: C, 60.07; H, 4.24; N, 10. 15; S, 11.62. Found: C, 60.22; H, 4.48;N, 10.05; S, 11.49.

Example 31(d):6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0554]

[0555] Example 31 (d) was prepared in a similar manner to that describedfor Example 31(a) except that 1-ethyl-3-methyl-1H-pyrazole-5-carboxylicacid was used in place of benzoic acid in step (ii). ¹H NMR (DMSO-d₆) δ13.15 (s, 1H), 10.18 (s, 1H), 8.61 (d, 1H, J=3.7 Hz), 8.22 (d, 1H, J=8.8Hz), 7.94 (d, 1H, J=16.3 Hz), 7.82 (t, 1H, J=7.5 Hz), 7.67 (d, 1H, J=7.7Hz), 7.55 (m, 3H), 7.40 (t, 1H, J=8.1 Hz), 7.28 (m, 1H), 7.06 (s, 1H),7.01 (d, 1H, J=8.8 Hz), 6.89 (d, 1H, J=7.9 Hz), 6.78 (s, 1H), 4.38 (q,2H, J=7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H, J=7.1 Hz). Anal. Calc forC₂₇H₂₄N₆0₂ 0.6 EtOAc C, 68.25; H, 5.61; N, 16.24. Found: C, 68.28; H,5.88; N, 16.01.

Example 31(e):6-[3-((1-Methylimidazol-2-yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0556]

[0557] Example 31 (e) was prepared in a similar manner to that describedfor Example 31(a) except that 1-methyl-1H-imidazole-2-carboxylic acidwas used in place of benzoic acid in step (ii). ¹H NMR (DMSO-d₆) δ 13.13(s, 1H), 10.47 (s, 1H), 8.60 (d, 1H, J=3.9 Hz), 8.21 (d, 1H, J=8.7 Hz),7.93 (d, 1H, J=16.3 Hz), 7.82 (t, 1H, J=7.6 Hz), 7.65 (m, 3H), 7.56 (d,1H, J=16.3 Hz), 7.43 (s, 1H), 7.37 (t, 1H, J=8.1 Hz), 7.28 (m,1H), 7.04(m, 3H), 6.84 (d, 1H, J=7.7 Hz), 3.95 (s, 3H). Anal. Calc forC₂₅H₂₀N₆O₂.0.4 H₂O: C, 67.49; H, 4.80; N, 18.65. Found:C, 67.68; H,4.73; N, 18.94.

Example 31(f):6-[3-((l-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(1,2-dimethyl-1H-imidazol-4-yl)ethenyl]-1H-indazole

[0558]

[0559] Example 31 (f) was prepared in a similar manner to that describedfor Example 31(a) except that(E)-3-(1,2-dimethyl-1H-imidazol-4-yl)acryloyl chloride hydrochloride wasused in place of (E)-3-pyridin-2-yl-acryloyl chloride hydrochloride instep (i) and 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid was used inplace of benzoic acid in step (ii). ¹H NMR (DMSO-d₆) δ 12.82 (s, 1H),10.17 (s, 1H), 8.05 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=8.4 Hz), 7.48 (s,1H), 7.38 (t, 1H, J=8.1 Hz), 7.25 (s, 2H), 7.20 (s, 1H), 7.01 (s, 1H),6.92 (d, 1H, J=8.7 Hz), 6.85 (d, 1H, J=8.7 Hz), 6.78 (s, 1H), 4.37 (q,2H, J=7.0 Hz), 3.56 (s, 3H), 2.31 (s, 3H), 2.19 (s, 3H), 1.29 (t, 3H,J=7.0 Hz). Anal. Calc for C₂₇H₂₇N₇0₂ 1.0 H₂0 0.3 EtOAc: C, 64.39; H,6.02; N, 18.64. Found: C, 64.52; H, 5.98; N, 18.52.

Example 32(a):6-[3-benzamidophenoxy]-3-E-[2-(1H-indazol-4-yl)ethenyl]-1H-indazole

[0560]

[0561] To a stirred solution of the6-(3-benzamidophenoxy)-3-E-[2-(1-(2-trimethylsilanyl-ethoxy)-methyl-imidazol-4-yl)ethenyl]-1H-indazolecompound (213 mg, 0.39 mmol) in 5 mL of THF was added 1.0 M TBAF in THF(6.0 ml, 6.0 mmol) and ethylenediamine (0.26 ml, 3.86 mmol). Afterheating at 70° C. for 18 h, the reaction mixture was cooled, dilutedwith EtOAc, and washed repeatedly with sat NaHCO₃ solution. The organiclayer was dried over MgSO₄ and conc. under reduced pressure. The residuewas flash chromatographed on silica gel eluting CH₂Cl₂:EtOAc: MeOH(1:1:0.2). The oil obtained was triturated from EtOAc/hexanes to giveAG13853 (65 mg, 40%). ¹H NMR (DMSO-d₆) δ 12.90 (s, 1H), 12.35 (s, 1H),10.32 (s, 1H), 8.08 (d, 1H, J=8.7 Hz), 7.91 (d, 2H, J=6.8 Hz), 7.81 (s,1H), 7.64-7.49 (m, 5H), 7.42-7.31 (m, 4H), 7.03 (s, 1H), 6.96 (d, 1H,J=8.7 Hz), 6.85 (d, 1H, J=8.1 Hz). Anal. Calc for C₂₅H₁₉N₅O₂.0.7 H₂O.0.4EtOAc: C, 68.07; H, 5.07; N, 14.92. Found: C, 67.93; H, 4.89; N, 15.06.

[0562] The starting material was prepared in a similar manner to thatdesribed for Example 31(a) except that(E)-3-{l-(²-trimethylsilanyl)-ethoxymethyl)-1H-imidazol-4-yl]-acryloylchloride hydrochloride was used in place of (E)-3-pyridin-2-yl-acryloylchloride hydrochloride in step (i).

Example 32(b):6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(1H-imidazol-4-yl)ethenyl]-1H-indazole

[0563]

[0564] Example 32(b) was prepared in a similar manner to that describedfor Example 32(a) except that 1-ethyl-3-methyl- 1H-pyrazole-5-carboxylicacid was used in place of benzoic acid in step (ii). ¹H NMR (DMSO-d₆) δ12.89 (s, 1H), 12.37 (s, 1H), 10.18 (s, 1H), 8.07 (d, 1H, J=8.9 Hz),7.74 (s, 1H), 7.58 (d, 1H, J=8.3 Hz), 7.49 (s, 1H), 7.44-7.32 (m, 3H),7.28 (s, 1H), 7.01 (s,1H), 6.95 (d, 1H, J=8.9 Hz), 6.86 (d, 1H, J=8.6Hz), 6.78 (s, 1H), 4.38 (q, 2H, J=7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H,J=7.1 Hz). Anal. Calc for C₂₅H₂₃N₇0₂-0.8 H₂0 0.1 EtOAc: C, 63.99; H,5.37; N, 20.57. Found: C, 63.72; H, 5.12; N, 20.25.

Example 32(c):6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(2-methylimidazol4-yl)ethenyl]-1H-indazole

[0565]

[0566] Example 32(c) was prepared in a simialr manner to that describedfor 32(b) except that(E)-3-[2-methyl-1-(2-trimethylsilanyl)-ethoxymethyl)-1H-imidazol4-yl]-acryloylchloride hydrochloride was used in place of(E)-3-[1-(2-trimethylsilanyl)-ethoxymethyl)-1H-imidazol-4-yl]-acryloylchloride hydrochloride in step (i). ¹H NMR (DMSO-d₆) δ 12.85 (bs, 1H),11.80 (bs, 1H), 10.18 (s, 1H), 8.05 (d, 1H, J=8.7 Hz), 7.58 (d, 1H,J=8.4 Hz), 7.48 (s, 1H), 7.39 (t, 1H, J=8.2 Hz), 7.33-7.05 (m, 3H), 7.00(s,1H), 6.93 (d, 1H, J=8.7 Hz), 6.86 (d, 1H, J=8.2 Hz), 6.78 (s, 1H),4.38 (q, 2H, J=7.1 Hz), 2.31 (s, 3H), 2.19 (s, 3H), 1.29 (t, 3H, J=7.1Hz). Anal. Calc for C₂₆H₂₅N₇O₂.0.9 H₂O 0.4 EtOAc: C, 63.87; H, 5.83; N,18.89. Found: C, 63.64; H, 5.76; N, 18.85.

Example 33(a):6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole

[0567]

[0568] Example 33(a) was prepared from6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazolein a similar manner to that described for Example 11. R_(f) sm 0.8, p0.15 (ethyl acetate); ¹H NMR (300 MHz, dmso-d6) δ 13.45 (s, 1H), 8.72(d, 1H, J=3.9 Hz), 8.47 (m, 1H), 8.31 (d, 1H, J=8.5 Hz), 8.06 (d, 1H,J=16.4 Hz), 7.92 (dt, 1H, J=1.7, 7.6 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.71(s, 1H), 7.68 (d, 1H, J=16.5 Hz), 7.61 (dd, 1H, J=1.7, 7.2 Hz),7.45-7.36 (m, 3H), 7.31 (d, 1H, J=8.5 Hz), 7.17 (m, 1H), 2.89 (d, 3H,J=4.6 Hz); 13C NMR (75 MHz, dmso-d6) δ 167.8, 154.8, 149.5, 141.9,141.8, 137.0, 136.8, 135.4, 132.5, 130.2, 130.0, 129.2, 127.7, 126.1,125.4, 123.5, 122.5, 122.4, 121.6, 120.2, 114.5; LCMS (100% area) Rt=3.5min (pos) [M+H]/z Calc'd 387, found 387. Analyzed with 0.1 H₂O, 0.1EtOAc Calc'd, C (67.78), H (4.82), N (14.11), S (8.08). Found: C(67.78), H (4.77), N (14.06), S (8.08). The starting material wasprepared as follows:

[0569] Under argon,6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (30.0g, 62.9 mmol) prepared in Example 14, step (i), was dissolved indichloromethane (375 mL) and was cooled to -42° C. in an acetonitile-dryice bath. Ozone was then bubbled through the mix (1 Umin, 60 V, 1.8Amps) for 45 min. Standard indicators did not give a clear color changedue to the solutions background color. To avoid over-oxidation, thereactions progress was monitored by TLC (1:9 EtOAc-Hex). The ozoneaddition was stopped and the flask was flushed with argon. Dimethylsulfide (30 mL) was then added and the mixture was allowed to warm to23° C. This mixture was stirred for 4h and was concentrated underreduced pressure. The oil was placed under high vacuum for 16 h. Theresidue was dissolved in dichloromethane (15 mL) and was diluted withhexane (100 mL) to give some crystals (not desired product). The mixturewas filtered and the filtrate was concentrated. The residue wasdissolved in 8:2 Hex-EtOAc (250 mL), treated with 50 mL silica.,filtered, and concentrated.6-Iodo-3-carboxaldehyde-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazoleformed as a yellow solid after 72 h under high vacuum (24.17 g, ˜95%pure by NMR, 91% yield): R_(f) sm 0.34, p 0.29 (ethyl acetate-hexane1:9); ¹H NMR (300 MHz, CDCl₃) δ 10.25 (s, 1H), 8.09 (s, 1H), 8.05 (d,1H), 7.80 (d, 1H), 5.88 (s, 2H), 3.71 (t, 2H), 0.93 (t, 2H), 0.0 (s,9H).

[0570]6-Iodo-3-carboxaldehyde-1-[2-(trimethyl-silanly)-ethoxymethyl]-1H-indazole(24.0 g, 59.7 mmol) was dissolved in THF (350 mL) and was cooled to −5°C. To this was added solid 2-picolyltriphenylphosphoniumchloride-potassium hydride (45.7 g, 100 mmol, 1.68 equiv). The reactionmixture was allowed to stir for 45 min. To the mixture, was added 3N HCl(20 mL) followed by saturated aqueous sodium bicarbonate (50 mL) to givea pH of 6. Excess THF was removed under reduced pressure and the residuewas partitioned between ethyl acetate and water. The organics werewashed with saturated aqueous sodium bicarbonate, water and the organiclayer was separated, dried over sodium sulfate, decanted andconcentrated under reduced pressure. The residue was taken up in 1:9ethyl acetate-hexane and was filtered. The filtrate was purified bysilica gel chromatography (2L silica, 20 to 30 to 50% ethylacetate-hexane) to give6-Iodo-3-E-[2-(pyridin-2-yl)ethenyl-1-[2-(trimethyl-silanly)-ethoxymethyl]-1H-indazole(18.9 g, 66% yield): R_(f) sm 0.52, p 0.25 (ethyl acetate-hexane 2:8);¹H NMR (300 MHz, CDCl₃) δ 8.64 (m, 1H), 8.00 (d, 1H, J=0.7 Hz), 7.87 (d,1H, J=16.4 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.69 (td, 1H, J=7.7, 1.8 Hz),7.55 (d, 1H, J=16.4 Hz), 7.55 (dd, 1H, J=8.5, 1.3 Hz), 7.47 (d, 1H,J=7.9 Hz), 7.18 (dd, 1H, J=1.1, 4.8 Hz), 5.70 (s, 2H), 3.59 (t, 2H,J=8.2 Hz), 0.90 (t, 2H, J=8.2 Hz), −0.04 (s, 9H); ¹³C NMR (75 MHz,CDCl₃) δ 156.8, 151.2, 144.2, 143.6, 138.0, 132.3, 132.2, 124.4, 124.0,123.8, 123.7, 123.5, 120.7, 94.1, 79.4, 68.1, 19.17, 0.0.

[0571] In a 200 mL round bottom flask was weighed cesium carbonate (13.7g, 41.9 mmol, 2.5 equiv) and this salt was dried under high vacuum witha heat gun. The catalyst [Pd(dppf)Cl₂—CH₂Cl₂] (1.37 g, 1.68 mmol, 0.1equiv) and6-Iodo-3-E-[2-(pyridin-2-yl)ethenyl-1-[2-(trimethyl-silanly)-ethoxymethyl]-1H-indazole(8.0 g, 16.76 mmol) were then added and the mix was taken up in DMF (71mL). To this mixture was added methyl thiosalicylate (4.62 mL, 33.5mmol, 2.0 equiv) and the vessel was warmed to 85° C. for 4.5 h. Thismixture was cooled to 23° C., was partitioned between ethyl acetate (350mL) and 50%-saturated aqueous sodium bicarbonate (300 mL). The organicswere washed with 10% sodium bisulfite (200 mL), brine and the organiclayer was separated. The organic material was dried over sodium sulfate,decanted and concentrated under reduced pressure. Purification by silicagel chromatography (500 mL silica; 30 to 40 to 50% ethyl acetate-hexane)gave6-[(2-methoxycarbonylphenyl)sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole(6.44 g, 74%): R_(f) sm 0.52, p 0.19 (ethyl acetate-hexane 3:7); FTIR(thin film) 2950, 2887, 2356, 1713, 1585, 1464, 1433, 1250, 1076, 837cm⁻¹; H NMR (300 MHz, CDCl₃) δ 8.70 (d, 1H), 8.12 (d, 1H), 8.04 (d, 1H),7.99 (d, 1H, J=16.4 Hz), 7.90 (s, 1H), 7.88 (t, 1H), 7.76 (d, 1H,jJ=16.4 Hz), 7.62 (d, 1H), 7.55 (d, 1H), 7.30-7.15 (m, 3H), 6.92 (d,1H), 5.80 (s, 2H), 4.01 (s, 3H), 3.78 (t, 2H), 0.96 (t, 2H), −0.03 (s,9H); ¹³C NMR (75 MHz, CDCl₃) 8 168.3, 156.8, 151.2, 144.3, 144.2, 143.2,138.0, 133.8, 133.6, 132.5, 132.4, 129.9, 129.3, 128.5, 126.0, 124.7,124.6, 123.8, 123.5, 118.3, 79.4, 68.2, 53.7,19.2, 0.0; LCMS (100% area)Rt=4.4 min, (pos) [M+H]/z Calc'd 518.2, found 518.2.

[0572] To6-[(2-methoxycarbonylphenyl)sulfanyl]-3-E-[2-(pyridin-²-yl)ethenyl]-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole(8.50 g, 16.4 mmol) was added THF (120 mL), methanol (120 mL), water(120 mL) and potassium carbonate (15.9 g, 115 mmol, 7.0 equiv). Thismixture was heated to 67° C. and was stirred for 22 h. The mixture wascooled and the excess solvents were removed. The residue was partitionedbetween ethyl acetate (300 mL) and water (250 mL). The aqueous wasacidified with 20% citric acid to pH 5 (˜70 mL) and the aqueous wasdrained. The organic layer was washed with water (50 mL) and hexane (100mL) was added to help precipitate the crystals that were forming in theethyl acetate layer. The solid was filtered and dried to give6-[(2-carboxyphenyl)sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1-[2-(trimethyl-silanyl)ethoxy-methyl]-1H-indazole(7.56 g, 91%): R_(f) sm 0.67, p 0.41 (ethyl acetate-hexane 8:2); ¹H NMR(300 MHz, CDCl₃) δ 8.60 (m, 1H), 8.10 (d, 1H, J=8.4 Hz), 8.04 (dd, 1H,J=1.7, 7.7 Hz), 7.85 (d, 1H, J=16.5 Hz), 7.83 (s, 1H), 7.70 (dt, 1H,J=1.7, 7.7 Hz), 7.59 (d, 1H, J=16.5 Hz), 7.52 (d, 1H, J=7.9 Hz), 7.38(dd, 1H, J=1.3, 8.4 Hz), 7.22-7.10 (m, 3H), 6.80 (dd, 1H, J=1.0, 8.0Hz), 3.59 (t, 2H, J=8.1 Hz), 0.85 (t, 2H, J=8.8.1 Hz), -0.1 (s, 9H).

[0573]6-[(2-Carboxyphenyl)sulfanyl-1-3-E-[2-(pyridin-2-yl)ethenyl]-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole(820 mg, 1.63 mmol) was dissolved in DMF (5 mL) and was treated withmethyl amine (2M in THF, 4.1 mL, 8.13 mmol, 50 equiv) and with HATU (929mg, 2.44 mmol, 1.5 equiv). This mixture was stirred for 30 min, waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate and the organic layer was separated. The organic materialwas dried over sodium sulfate, decanted and concentrated under reducedpressure. Purification by silica gel chromatography (50 mL silica; 60 to70% ethyl acetate-hexane) gave6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazoleas a solid (795 mg, 94%): R_(f) sm 0.35, p 0.23 (ethyl acetate-hexane6:4); FTIR (thin film) 3306, 2951, 1643, 1606, 1587, 1563, 1469, 1433,1410, 1303, 1249, 1217, 1075, 836 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.70(m, 1H), 8.06 (d, 1H, J=8.4 Hz), 7.94 (d, 1H, J=16.3 Hz), 7.74 (dt, 1H,J=1.8, 7.7 Hz), 7.70-7.60 (m, 3H), 7.52 (d, 1H, J=7.9 Hz), 7.35-7.20 (m,5H), 6.45 (bs, 1H), 5.80 (s, 2H), 3.62 (t, 2H), 3.00 (d, 3H), 0.93 (t,2H), -0.05 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 179.7, 169.9, 156.8,151.1, 144.2, 143.0, 138.1, 136.1, 135.4, 133.2, 132.2, 132.1, 130.2,128.5, 127.2, 124.7, 124.1, 123.8, 123.5, 123.3, 114.9, 68.1, 28.2,19.2, 0.00; LCMS (100% area) Rt=4.15 min, (pos) [M+H]/z Calc'd 517.2,found 517.2

Example 33(b):6-[2-(2-methylquinol-6-ylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0574]

[0575] Example 33(b) was prepared in a similar manner to that describedfor Example 33(a) except that, in step (v), ⁶-amino-2-methylquinolinewas used instead of methylamine: ¹H NMR (300 MHz, CDCl₃) δ 10.2 (bs,1H), 8.64 (m, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.98-7.80 (m, 4H), 7.69(dt, 1H, J=1.7, 7.7 Hz), 7.55-7.40 (m, 7H), 7.25-7.16 (m, 3H), 2.71 (s,3H).

Example 33(c):6-[2-(phenylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0576]

[0577] Example 33(c) was prepared in a similar manner to that describedfor Example 33(a) except that, in step (v), aniline was used instead ofmethyl amine: ¹H NMR (300 MHz, dmso-d6) δ 13.35 (s, 1H), 10.53 (s, 1H),8.67 (m, 1H), 8.22 (d, 1H, J=7.5 Hz), 7.99 (d, 1H, J=16.4 Hz), 7.85 (dt,1H, J=1.8, 7.6 Hz), 7.80-7.55 (m, SH), 7.45-7.10 (m, 9H); LCMS (100%area) Rt=3.86, (pos) [M+H]/z Calc'd 449.1, found 449.1. Analyzed with0.41 H₂O Calc'd, C (71.13), H (4.60), N (12.29), S (7.03). Found: C(71.04), H (4.62), N (12.31), S (7.01).

Example 33(d):6-[2-(3-chlorophenylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0578]

[0579] Example 33(d) was prepared in a similar manner to that describedfor Example 33(a) except that, in step (v), 3-chloroaniline was usedinstead of methyl amine: 1H NMR (300 MHz, CDCl₃) δ 8.53 (m, 1H), 7.92(d, 1H, J=8.4 Hz), 7.77 (d, 1H, J=16.4 Hz), 7.68 (dt, 1H, J=1.7, 7.7Hz), 7.64-7.56 (m, 2H), 7.51-7.43 (m, 3H), 7.35-7.28 (m, 4H), 7.19-7.12(m, 3H), 7.02 (m, 1H); LCMS (100% area) Rt 3.98 min, (pos) [M+H]/zCalc'd 483.1, found 483.1. Analyzed with 0.3 H20 Calc'd, C (66.40), H(4.05), N (11.47), S (6.57). Found: C (66.36), H (4.08), N (11.49), S(6.55).

Example 33(e):6-[2-(cyclopropylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H--1H-indazole

[0580]

[0581] Example 33(e) was prepared in a similar manner to that describedfor Example 33(a) except that, in step (v), cyclopropylamine was usedinstead of methylamine: ¹H NMR (300 MHz, dmso-d6) δ 13.45 (s, 1H), 8.73(d, 1H, J=3.9 Hz), 8.56 (d, 1H, J=4.3 Hz), 8.31 (d, 1H, J=8.5 Hz), 8.08(d, 1H, J=16.4 Hz), 7.91 (dt, 1H, J=1.7, 7.7 Hz), 7.78 (d, 1H, J=7.8Hz), 7.70 (m, 2H), 7.57 (m, 1H,), 7.40 (m, 3H), 7.30 (d, 1H, J=8.4 Hz),7.20 (d, 1H, J=7.8 Hz), 2.94 (m, 1H), 0.80 (m, 2H), 0.65 (m, 2H); LCMS(100% area) Rt 3.51 min, (pos) [M+H]/z Calc'd 413.1, found 413.1.

Example 33(f):6-[2-(2,2,2-trifluoroethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0582]

[0583] Example 33(f) was prepared in a similar manner to that describedfor Example 33(a) except that, in step (v), 2,2,2-trifluoroethylaminewas used instead of methylamine: ¹H NMR (300 MHz, dmso-d6) δ 13.5 (s,1H), 9.29 (t, 1H, J=6.3 Hz), 8.74 (m, 1H), 8.37 (d, 1H, J=8.3 Hz), 8.10(d, 1H, J=16.4 Hz), 7.94 (dt, 1H, J=1.8, 7.6 Hz), 7.80 (d, 1H, J=7.9Hz), 7.75-7.65 (m, 3H), 7.55-7.40 (m, 3H), 7.33 (d, 1H), 7.22 (d, 1H),4.22 (m, 2H); LCMS (100% area) Rt=3.70 min, (pos) [M+H]/z Calc'd 455.1,found 455.1.

Example 33(g):6-[2-(carboxy)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H--1H-indazole,tetrabutylammonium salt

[0584]

[0585] Example 33(g) was prepared in a similar manner to that describedfor Example 33(a) except that step (v) was omitted: R_(f) sm 0.41, p 0.0(ethyl acetate-hexane 8:2); ¹H NMR (300 MHz, dmso-d6) δ 8.75 (m, 1H),8.25 (d, 1H, J=8.6 Hz), 8.05 (d, 1H, 16.4 Hz), 7.88 (dt, 1H, J=1.8, 7.8Hz), 7.83-7.60 (m, 4H), 7.33 (m, 2H), 7.16 (m, 2H),6.70 (m, 1H), 3.30(m, 8H), 1.70 (m, 8H), 1.42 (m, 8H), 1.05 (t, 12H); LCMS (100% area) Rt3.24 (pos) [M+H (acid component only)]/z Calc'd 374.1, found 374.1.Analyzed with 0.1 H₂O Calc'd, C (72.07), H (8.21), N (9.09), S (5.20).Found: C (72.04), H (8.29), N (9.06), S (5.12).

Example 33(h):6-[2-(3-chlorophenylcarbamoyl)phenylsulfanyl]-3-Z-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0586]

[0587] Example 33(h) was prepared in the same reaction as Example 33(d).It should be noted that, although this compound was isolated andcharacterized pure, it was found to isomerize to Example 33(d) underassay conditions. ¹H NMR (300 MHz, CDCl₃) δ 8.82 (m, 1H), 8.31 (s, 1H),7.86 (m, 2H), 7.77 (m, 2H), 7.61 (t, 1H, J=2.0 Hz), 7.46 (d, 1H, J=8.0Hz), 7.33 (m, 5H), 7.21 (t, 1H, J=8.0 Hz), 7.13 (dd, 1H, J=1.5, 8.1 Hz),7.08 (m, 1H), 6.98 (d, 1H, J=13.0 Hz), 6.66 (d, 1H, J=13.1 Hz); LCMS(100% area) Rt 4.40 min, (pos) [M+H]/z Calc'd 483.1, found 483.1.Analyzed with 0.3 H₂O Calc'd, C (66.40), H (4.05), N (11.47), S (6.57).Found: C (66.36), H (4.08), N (11.49), S (6.55).

Example 34:⁶-[²-((RS-(trans-2-phenylcyclopropyl)carbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0588]

[0589] Example 33(g) was converted to Example 34 in a similar manner tothat described for Example 33(a), step (v) except thattrans-2-phenylcyclopropylamine was used instead of methylamine: FTIR(thin film) 1704, 1638, 1584, 1559, 1530, 1497, 1460, 1430, 1339, 1306,1269, 1223, 1152, 1086, 1061, 966, 844 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ13.3 (s, 1H), 8.71 (d, 1H, J=4.4 Hz), 8.61 (d, 1H, J=3.9 Hz), 8.20 (d,1H, J=8.5 Hz), 7.96 (d, 1H, J=16.4 Hz), 7.81 (dt, 1H, J=1.7, 7.6 Hz),7.66 (d, 1H, J =7.8 Hz), 7.59-7.50 (m, 3H), 7.37-7.25 (m, 5H), 7.21-7.08(m, 5H), 3.01 (m, 1H), 2.03 (m, 1H), 1.25 (m, 2H); LCMS (100% area)Rt=3.72 min, (pos) [M+H]/z Calc'd 489.2, found 489.2. Analyzed with 0.6MeOH, 0.16 CH₂Cl₂ Calc'd, C (70.86), H (5.17), N (10.75), S (6.15).Found: C (70.87), H (5.18), N (10.75), S (5.96).

Example 35(a):6-[2-(n-Propylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0590]

[0591]6-[2-(Pentafluorophenoxycarbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H--indazole(60 mg, 0.1112 mmol) was dissolved in DMF (0.8 mL), treated withn-propylamine (11 μL, 0.1335 mmol) and stirred at room temperature. HPLCanalysis after 15 minutes indicated that all staring material had beenconsumed. The reaction mixture was concentrated by high vacuum rotaryevaporation, giving a solid. The solid was sonicated with CH₂Cl₂ givinga fine suspension, which was filtered, and rinsed with CH₂Cl₂ to provide40 mg (87% yield) of the title compound. ¹H NMR (DMSO-d₆) δ 13.31 (s,1H), 8.60 (d, J=4.0 Hz, 1H), 8.41 (t, J=6.2 Hz, 1H), 8.19 (d, J=8.5 Hz,1H), 7.94 (m, 3H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (t, J=8.7 Hz, 1H),7.56 (m, 2H), 7.47 (m, 1H), 7.30 (m, 3H), 7.18 (d, J=8.3 Hz, 1H), 3.20(q, J=6.0 Hz, 2H), 1.55 (septet, J=5.9 Hz, 2H), 0.92 (t, J=6.0 Hz, 3H).Anal. Calcd. for C₂₄H₂₂N₄OS.(1.5 H₂O, 0.8 DMF): C, 63.41; H, 6.17; N,13.45; S, 6.41. Found: C, 63.37; H, 5.68; N, 13.44; S, 6.32.

[0592] The starting material was prepared as follows:

[0593] A solution of the tetrabutyl ammonium salt of6-(2-carboxyphenylsulfanyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole)(615 mg, 1.0 mmol) dissolved in dry DMF (10.0 ml) was treated withpyridine (89 μL, 1.1 mmol), and pentafluorophenyl trifluoroacetate (206μL, 1.2 eq), at room temperature, under an argon atmosphere. HPLCanalysis after 45 minutes showed mostly unreacted carboxylic acid, soadditional pyridine (89 μL, 1.1 mmol), and pentafluorophenyltrifluoroacetate (206 μL, 1.2 eq) were added. HPLC analysis 15 minuteslater indicated that starting acid had been completely consumed. Thereaction mixture was concentrated under high vacuum rotary evaporation,then triturated with CH₂Cl₂ (˜1 mL) causing the formation of crystals,which were collected by filtration, rinsed with additional CH₂Cl₂, anddried. The mass of the bright yellow crystals was 336 mg. The remainingfiltrate was concentrated and purified by flash chromatography (10%acetontrile/CH₂Cl₂ to 80% acetonitrile/CH₂Cl₂), yielding an additional70 mg of solid. The total yield of6-[2-(Pentafluorophenoxycarbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H--indazolewas 406 mg, or 89%. ¹H NMR (CDCl₃) δ 10.22 (1H, bs), 8.66 (1H, d, J=4.5Hz), 8.28 (2H, dd, J=7.7. 1.5 Hz), 8.15 (1H, d, J=8.5 Hz), 7.97 (1H, d,J=16.2 Hz), 7.79 (1H, s), 7.15-7.75 (7H, m), 6.92 (1H, d, J=8.1 Hz).

Example 35(b):6-[2-(i-Propylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yI)ethenyl]-1H-indazole

[0594]

[0595] Example 35(b) was prepared in a similar manner to that describedfor Example 35(a) except that isopropylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆)δ 13.30(s, 1H), 8.60(d,J=4.5 Hz, 1H),8.26 (d,J=7.34 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.94 (d, J=16.4 Hz, 1H),7.80 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.56 (m, 2H), 7.45(m, 1H), 7.30 (m, 3H), 7.18 (d, J=8.5 Hz, 1H), 7.08 (m, 1 H), 4.04(septet, J=7.4 Hz, 1H), 1.15 (d, J=6.6 Hz, 6H). Anal. Calcd. forC₂₄H₂₂N₄0S-1.7 H₂O: C, 64.75; H, 5.75; N, 12.59; S, 7.20. Found: C,64.79; H, 5.36; N, 12.74; S, 7.08.

Example 35(c):6-[2-(Cyclobutylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0596]

[0597] Example 35(c) was prepared in a similar manner to that describedfor Example 35(a) except that cyclobutylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.62 (m, 2H), 8.19 (d,J=8.5 Hz, 1H), 7.94 (m, 2H), 7.80 (dt, J=1.7, 7.5 Hz, 1H), 7.65 (t,J=8.1 Hz, 1H), 7.56 (s, 1H), 7.47 (m, 1H), 7.30 (m, 3H), 7.17 (d, J=8.3Hz, 1H), 4.36 (septet, J=8.1 Hz, 1H), 2.22 (m, 2H), 2.03 (m, 2H), 1.67(m, 2H). Anal. Calcd. for C₂₅H₂₂N₄0S-(0.5 H₂0, 0.9 DMF): C, 66.36; H,5.89; N, 13.69; S, 6.40. Found: C, 66.21; H, 5.78; N, 13.82; S, 6.36.

Example 35(d):6-(2-Carbamoylphenylsulfanyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0598]

[0599] Example 35(d) was prepared in a similar manner to that describedfor Example 35(a) except that ammonia was used instead-of n-propylamine.¹H NMR (DMSO-d₆) δ 8.60 (d, J=4.9 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H), 7.94(m, 3H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.60 (m, 4H), 7.48 (bs, 1H), 7.25(m, 4H), 7.0 (m, 1H). Anal. Calcd. for C₂₁H₁₆N₄OS.0.25 H₂O: C, 66.91; H,4.41; N, 14.86; S, 8.51. Found: C, 66.99; H, 4.40; N, 15.10; S, 8.49.

Example 35(e):6-[2-((1-methylpyrrol-2-ylhydrazido)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0600]

[0601] Example 35(e) was prepared in a similar manner to that describedfor Example 35(a) except that 1-methylpyrrol-2-ylhydrazide was usedinstead of n-propylamine. ¹H NMR (DMSO-d₆) δ 13.34 (s, 1H), 10.25 (s,1H), 10.05 (s, 1H), 8.60 (d, J=4.5 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.95(d, J=16.2 Hz, 1H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (m, 3H), 7.57 (d,J=16.0 Hz, 1H), 7.43-7.18 (m, 4H), 7.07 (d, J=7.9 Hz, 1H), 7.00 (d,J=3.4 Hz, 2H), 6.07 (t, J=3.2 Hz, 1H), 3.88 (s, 3H). Anal. Calcd. forC₂₇H₂₂N₆O₂S.0.6 H₂O: C, 64.17; H, 4.63; N, 16.63; S, 6.34. Found: C,64.24; H, 4.48; N, 16.56; S, 6.28.

Example 35(f):6-[2-((2-fluorobenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0602]

[0603] Example 35(f) was prepared in a similar manner to that describedfor Example 35(a) except that 2-fluorobenzyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.99(t, J=5.8 Hz, 1H),8.61 (d, J=4.5 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 7.94 (d, J=16.2 Hz, 1H),7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.56 (m, 3H), 7.47(t, J=7.9 Hz, 1H), 7.31 (m, 4H), 7.15 (m, 4H), 4.51 (d, J=5.7 Hz, 2H).Anal. Calcd. for C₂₈H₂₁FN₄OS-0.25 H₂O: C, 69.33; H, 4.47; N, 11.55; S,6.61. Found: C, 69.32; H, 4.41; N, 11.58; S, 6.59.

Example 35(g):6-[2-((4-Methoxybenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0604]

[0605] Example 35(g) was prepared in a similar manner to that describedfor Example 35(a) except that 4-methoxybenzyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.90 (t, J=5.5 Hz, 1H),8.60 (d, J=4.2 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.95 (d, J=16.3 Hz, 1H),7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.55 (m, 3H), 7.30(m, 5H), 7.18 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 4.39 (d, J=6.0Hz, 2H), 3.72 (s, 3H). Anal. Calcd. for C₂₉H₂₄N₄O₂S.0.6 H₂O: C, 69.19;H, 5.05; N, 11.13; S, 6.37. Found: C, 69.12; H, 4.85; N, 11.24; S, 6.35.

Example 35(h):6-[2-((5-Methylfur-2-yl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0606]

[0607] Example 35(h) was prepared in a similar manner to that describedfor Example 35(a) except that 5-methylfur-2-yl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.88 (t, J=5.3 Hz, 1H),8.60 (d, J=4.3 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.95 (d, J=16.3 Hz, 1H),7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.54 (m, 3H), 7.30(m, 4H), 7.18 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.1 Hz, 3H). Anal. Calcd.for C₂₇H₂₂N₄O₂S.0.4 H₂O: C, 68.45; H, 4.85; N, 11.83; S, 6.77. Found: C,68.35; H, 4.80; N, 11.85; S, 6.68.

Example 35(i):6-[2-(Benzyloxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0608]

[0609] Example 35(i) was prepared in a similar manner to that describedfor Example 35(a) except that 0-benzyl hydroxylamine was used instead ofn-propylamine. 1H NMR (DMSO-d₆) δ 13.31 (s, 1H), 11.64 (s, 1H), 8.90 (t,J=5.5 Hz, 1H), 8.60 (d, J=4.1 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.95 (d,J=16.3 Hz, 1H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H),7.56 (m, 2H), 7.50-7.24 (m, 9H), 7.17 (t, J=8.5 Hz, 2H), 4.94 (s, 2H).Anal. Calcd. for C₂₈H₂₂N₄0₂S-0.8 H20: C, 68.22; H, 4.83; N, 11.37; S,6.50. Found: C, 68.08; H, 4.65; N, 11.41; S, 6.47.

Example 35(j):6-[2-(Allyloxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0610]

[0611] Example 35(j) was prepared in a similar manner to that describedfor Example 35(a) except that 0-allyl hydroxylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.32 (s, 1H), 11.56 (s, 1H), 8.60 (d,J=4.1 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.95 (d, J=16.5 Hz, 1H), 7.81(dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.56 (m, 2H), 7.48-7.24(m, 5H), 7.16 (m, 2H), 6.00 (m, 1H), 5.37 (d, J=18.3 Hz, 1H), 5.27 (d,J=11.3 Hz, 1H), 4.42 (d, J=6.0 Hz, 1H). Anal. Calcd. forC₂₄H₂₀N₄O₂S.(0.2 H₂0, 0.2CH₂Cl₂): C, 65.35; H, 4.96; N, 12.10; S, 6.92.Found: C, 65.24; H, 4.50; N, 12.56; S, 7.17.

Example 35(k):6-[2-(Isopropoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0612]

[0613] Example 35(k) was prepared in a similar manner to that describedfor Example 35(a) except that 0-isopropyl hydroxylamine was used insteadof n-propylamine. 1H NMR (DMSO-d₆) δ 13.30 (s, 1H), 11.33 (s, 1H), 8.60(d, J=4.1 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.95 (d, J=16.5 Hz, 1H), 7.81(dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.55 (m, 2H), 7.48-7.24(m, 4H), 7.17 (d, J=8.3 Hz, 2H), 4.12 (septet, J=5.7 Hz, 1H), 1.21 (d,J=6.2 Hz, 6H. Anal. Calcd. for C₂₄H₂₂N₄O₂S.(0.4 H₂O, 0.7 CH₂Cl₂): C,59.67; H, 4.91; N, 11.27; S, 6.45. Found: C, 59.61; H, 4.81; N, 11.42;S, 6.45.

Example 35(1):6-[2-((4-Aminobenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0614]

[0615] Example 35(1) was prepared in a similar manner to that describedfor Example 35(a) except that ⁴-aminobenzyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.78 (t, J=6.0 Hz, 1H),8.60 (d, J=4.3 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.95 (d, J=16.3 Hz, 1H),7.85 (bs, 1H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H),7.59 (s, 1H), 7.51 (m, 2H), 7.30 (m, 3H), 7.19 (d, J=8.7 Hz, 1H), 7.05(m, 3H), 6.56 (d, J=8.7 Hz, 1H), 6.51 (d, J=8.5 Hz, 2H), 4.29 (d, J=6.0Hz, 2H). Anal. Calcd. for C₂₈H₂₃N₅OS.0.6 H₂O: C, 68.86; H, 4.99; N,14.34; S, 6.57. Found: C, 68.83; H, 4.80; N, 14.16; S, 6.52.

Example 35(m):6-[2-((Thien-2-ylhydrazido)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0616]

[0617] Example 35(m) was prepared in a similar manner to that describedfor Example 35(a) except that thien-2-ylhydrazide was used instead ofn-propylarnine. ¹H NMR (DMSO-d₆) δ 13.49 (bs, 1H), 10.64 (s, 1H), 10.47(s, 1H), 8.66 (d, J=4.0 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.08-7.82 (m,5H), 7.66 (m, 3H), 7.39 (m, 3H), 7.24 (m, 2H), 7.09 (d, J=8.1 Hz, 1H),7.00 (d, J=3.4 Hz, 2H), 6.07 (t, J=3.2 Hz, 1H), 3.88 (s, 3H). Anal.Calcd. for C₂₆H₁₉N₅O₂S₂1.5 H₂O: C, 59.52; H, 4.23; N, 13.35; S, 12.22.Found: C, 59.56; H, 4.42; N, 13.33; S, 11.75.

Example 35(n):6-[2-(N²-(pyrid-2-ylhydrazino)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0618]

[0619] Example 35(n) was prepared in a similar manner to that describedfor Example 35(a) except that 2-hydrazinopyridine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 10.30 (s, 1H), 8.60 (d,J=4.4 Hz, 1H), 8.48 (s, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.09 (d, J=4.9 Hz,1 H), 7.94 (d, J=16.4 Hz, 1 H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.67 (m,1H), 7.62-7.47 (m, 3H), 7.40 (m, 2H), 7.31-7.12 (m, 3H), 6.73 (m, 2H).Anal. Calcd. for C₂₆H₂₀N₆OS.0.3 H20: C, 66.45; H, 4.42; N, 17.88; S,6.82. Found: C, 66.33; H, 4.50; N, 17.78; S, 6.60.

Example 35(o): 6-[2-(N-Hydroxy-N-methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0620]

[0621] Example 35(o) was prepared in a similar manner to that describedfor Example 35(a) except that N-methyl hydroxylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.24 (s, 1H), 9.94 (s, 1H), 8.60 (d,J=4.0 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.92 (d, J=16.2 Hz, 1H), 7.80(dt, J=1.7, 7.5 Hz, 1H), 7.65 (t, J=8.5 Hz, 1H), 7.54 (d, J=16.5 Hz,1H), 7.47-7.24 (m, 6H), 7.16 (d, J=8.5 Hz, 1H) 3.24 (bs, 1H). Anal.Calcd. for C₂₂H₁₈N₄O₂S.(0.5 H₂0, 0.3 CH₂Cl₂): C, 61.29; H, 4.52; N,12.82; S, 7.34. Found: C, 61.24; H, 4.33; N, 12.67; S, 7.34.

Example 35(p):6-[2-((Pyrid-4-yl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0622]

[0623] Example 35(p) was prepared in a similar manner to that describedfor Example 35(a) except that 4-aminomethyl pyridine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (bs, 1H), 9.07 (t, J=6.8 Hz,1H), 8.60 (d, J=4.2 Hz, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.19 (d, J=8.7 Hz,1H), 7.95 (d, J=16.4 Hz, 1H), 7.80 (dt, J=1.7, 7.5 Hz, 1H), 7.68-7.52(m, 3H), 7.42 (m, 2H), 7.39-7.31 (m, 3H), 7.27 (m, 1H), 7.20-7.10 (m,2H), 4.48 (d, J=6.2 Hz, 2H).

Example 35(q):6-[2-((2-Methylphenylhydrazido)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0624]

[0625] Example 35(q) was prepared in a similar manner to that describedfor Example 35(a) except that 2-methylphenyl hydrazide was used insteadof n-propylamine. ¹H NMR (DMSO-d₆) δ 13.43 (bs, 1H), 10.45 (s, 1H),10.28 (s, 1H), 8.64 (d, J=4.0 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.01 (d,J=16.6 Hz, 1H), 7.92 (m, 1H), 7.81 (m, 1H), 7.69 (m, 1H), 7.60 (d,J=16.4 Hz, 1H), 7.50-7.22 (m, 8H), 7.07 (d, J=7.7 Hz, 1H), 2.45 (s, 3H).

Example 35(r):6-[2-(methoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0626]

[0627] Example 35(r) was prepared in a similar manner to that describedfor Example 35(a) except 0-methyl hydroxylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.32 (s, 1H), 11.60 (s, 1H), 8.60 (d,J=3.8 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.95 (d, J=16.2 Hz, 1H), 7.81(dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.56 (m, 2H), 7.47 (dd,J=7.4, 1.7 Hz, 1H), 7.43-7.24 (m, 3H), 7.17 (m, 2H), 3.72 (s, 3H). Anal.Calcd. for C₂₂H₁₈N₄O₂S-0.6 CH₂Cl₂: C, 59.86; H, 4.27; N, 12.36; S, 7.07.Found: C, 59.94; H, 4.40; N, 12.00; S, 6.80.

Example 35(s):6-[2-((Cyclopropyl)methoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0628]

[0629] Example 35(s) was prepared in a similar manner to that describedfor Example 35(a) except that 0-cyclopropyl hydroxylamine was usedinstead of n-propylamine. ¹H NMR (DMSO-d₆) δ 13.38 (s, 1H), 11.51 (s,1H), 8.64 (d, J=3.8 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.00 (d, J=16.4 Hz,1H), 7.86 (m, 2H), 7.63-7.52 (m, 2H), 7.49-7.29 (m, 4H), 7.17 (m, 2H),3.70 (d, J=7.2 Hz, 1H), 1.10 (m, 1H), 0.53 (m, 2H), 0.27 (m, 2H). Anal.Calcd. for C₂₅H₂₂N₄O₂S-1.6 H20: C, 63.70; H,5.39; N, 11.89; S, 6.80.Found: C, 63.58; H, 4.95; N, 11.71; S, 6.66.

Example 35(t):6-[2-(n-Propoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0630]

[0631] Example 35(t) was prepared in a similar manner to that describedfor Example 35(a) except that 0-n-propyl hydroxylamine was used insteadof n-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 11.48 (s, 1H), 8.60(d, J=3.8 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.95 (d, J=16.2 Hz, 1H), 7.81(dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.60-7.52 (m, 2H),7.49-7.24 (m, 4H), 7.17 (m, 2H), 3.84 (t, J=6.6 Hz, 2H), 1.62 (septet,J=6.4 Hz, 2H), 0.92 (t, J=6.1 Hz, 3H). Anal. Calcd. for C₂₄H₂₂N₄O₂S.(0.5H₂O, 0.25 CH₂Cl₂): C, 63.21; H, 5.14; N, 12.16; S, 6.96. Found: C,63.15; H, 5.13; N, 12.17; S, 6.99.

Example 35(u):6-[2-(Allylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0632]

[0633] Example 35(u) was prepared in a similar manner to that describedfor Example 35(a) except that allylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.60 (m, 2H), 8.19 (d,J=8.5 Hz, 1H), 7.93 (d, J=16.3 Hz, 3H), 7.79 (dt, J=1.7, 7.5 Hz, 1H),7.64 (m, 1H), 7.60-7.48 (m, 3H), 7.37-7.23 (m, 3H), 7.17 (d, J=8.5 Hz,1H), 7.07 (m, 1H), 5.87 (m, 1H), 5.25 (dq, J=17.33, 1.9 Hz, 1H), 5.09(dq, J=10.2, 1.9 Hz, 1H), 3.87 (m, 2H). Anal. Calcd. for C₂₄H₂₀N₄OS.0.8CH₂Cl₂: C, 62.00; H, 4.53; N, 11.66; S, 6.67. Found: C, 62.08; H, 4.73;N, 11.99; S, 6.66. MALDI FIMS (MH+) Calc'd, 413.1431, found 413.1449.

Example 35(v):6-[2-(Cyclopropylmethyl-carbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0634]

[0635] Example 35(v) was prepared in a similar manner to that describedfor Example 35(a) except that cyclopropylmethyl amine was used insteadof n-propylamine. 1H NMR (DMSO-d₆) δ 13.30 (s, 1H), 8.60 (d, J=4.0 Hz,1H), 8.48 (t, J=5.3 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.90 (d, J=16.4 Hz,1H), 7.80 (dt, J=1.7, 7.5 Hz, 1H), 7.67-7.45 (m, 4H), 7.33-7.23 (m, 3H),7.18 (d, J=8.3 Hz, 1H), 7.06 (m, 1H), 3.13 (t, J=6.2 Hz, 2H), 1.00 (m,1H), 0.41 (m, 1H), 0.24 (m, 1H). Anal. Calcd. for C₂₅H₂₂N₄OS.0.5 CH₂Cl₂:C, 65.30; H, 4.94; N, 11.95; S, 6.84. Found: C, 65.10; H, 4.93; N,12.04; S, 6.82. MALDI FTMS (MH+) Calc'd 427.1587, found 427.1605.

Example 35(w):6-[2-(Cyanomethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0636]

[0637] Example 35(w) was prepared in a similar manner to that describedfor Example 35(a) except that aminoacetonitrile was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.35 (s, 1H), 9.19 (t, J=5.3 Hz, 1H),8.60 (d, J=4.8 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H), 7.94 (d, J=16.4 Hz, 3H),7.79 (dt, J=1.7, 7.5 Hz, 1H), 7.70-7.50 (m, 4H), 7.41-7.23 (m, 3H), 7.18(d, J=8.5 Hz, 1 H), 7.06 (d, J=6.6 Hz, 1 H), 4.32 (d, J=5.5 Hz, 2H).MALDI FFMS (MH+) Calc'd 412.1227, found 412.1215.

Example 35(x):6-[2-(Ethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0638]

[0639] Example 35(x) was prepared in a similar manner to that describedfor Example 35(a) except that ethylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 8.60 (d, J=4.0 Hz, 1H), 8.40 (t, J=6.2Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.94 (m, 3H), 7.81 (dt, J=1.7, 7.5 Hz,1H), 7.68-7.44 (m, 3H), 7.56 (m, 2H), 7.30 (m, 3H), 7.17 (dd, J=8.1, 1.8Hz, 1H), 7.06 (m, 1H), 3.24 (m, 2H), 1.11 (t, J=7.0 Hz, 3H). Anal.Calcd. for C₂₃H₂₀N₄OS.(1.75 H₂0, 1.0 DMF): C, 61.82; H, 6.09; N, 13.87;S, 6.35. Found: C, 61.58; H, 5.66; N, 13.96; S, 5.93. MALDI FTMS (MH⁺)Calc'd 401.1431, found 401.1417.

Example 35(y):6-[2-(Thiazol-2-ylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0640]

[0641] Example 35(y) was prepared in a similar manner to that describedfor Example 35(a) except that 2-aminothiazole was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.32 (s, 1H), 12.67 (s, 1H), 8.60 (d,J=4.1 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.93 (d, J=16.3 Hz, 1H), 7.80(dt, J=1.7, 7.5 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H),7.60-7.51 (m, 3H), 7.49-7.34 (m, 2H), 7.26 (m, 2H), 7.18 (m, 2H). Anal.Calcd. for C₂₄H₁₇N₅OS₂.0.75 H₂O: C, 61.45; H, 3.98; N, 14.93; S, 13.67.Found: C, 61.35; H, 4.10; N, 14.96; S, 13.68.

Example 35(z):6-[2-(2-(Ethoxy)ethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0642]

[0643] Example 35(z) was prepared in a similar manner to that describedfor Example 35(a) except that 2-ethoxyethyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.30 (s, 1H), 8.60 (d, J=4.0 Hz, 1H),8.45 (t, J=6.2 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.93 (m, 2H), 7.80 (dt,J=1.7, 7.5 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.60-7.45 (m, 3H), 7.36-7.23(m, 3H), 7.17 (d, J=8.3 Hz, 1H), 7.07 (m, 1H), 3.50 (m, 6H), 1.10 (d,J=7.0 Hz, 3H). Anal. Calcd. for C₂₅H₂4N40₂S-0.5 CH₂Cl₂: C, 62.89; H,5.17; N, 11.50; S, 6.58. Found: C, 62.45; H, 5.33; N, 11.25; S, 6.55.

Example 35(aa):6-[2-((3-methoxybenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0644]

[0645] Example 35(aa) was prepared in a similar manner to that describedfor Example 35(a) except that 3-methoxybenzyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.30 (s, 1 H), 8.97 (t, J=5.5 Hz,1H), 8.60 (d, J=4.2 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 7.93 (d, J=16.3 Hz,1H), 7.80 (dt, J=1.7, 7.5 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.60-7.51 (m,3H), 7.38-7.15 (m, SH), 7.08 (m, 1H), 6.94 (m, 2H), 6.80 (dd, J=8.1, 1.5Hz, 1H), 4.44 (d, J=6.6 Hz, 2H), 3.71 (s, 3H). Anal. Calcd. forC₂₉H₂₄N₄O₂S-0.4 H₂O: C, 60.25; H, 4.50; N, 17.57; S, 8.04. Found: C,60.14; H, 4.47; N, 17.42; S, 8.00.

Example 35(bb):6-[2-((fur-2-yl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0646]

[0647] Example 35(bb) was prepared in a similar manner to that describedfor Example 35(a) except that 2-aminomethyl furan was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.93 (t, J=5.7 Hz, 1H),8.60 (d, J=4.3 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.93 (d, J=16.5 Hz, 1H),7.80 (dt, J=1.9, 7.4 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.59-7.48 (m, 4H),7.30 (m, 4H), 7.37-7.24 (m, 3H), 7.18(d, J=9.2 Hz, 1H),7.06(d,J=8.1 Hz,1H), 6.40 (m, 1H),6.31 (m, 1H),4.44(d,J=5.3 Hz, 2H). Anal. Calcd. orC26H2oN402S (0.1 H₂0, 0.75 CH₂Cl₂): C, 62.02; H, 4.22; N, 10.82; S,6.19. Found: C, 61.58; H, 4.30; N, 10.55; S, 6.12.

Example 35(cc):6-[2-(2-Propynylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0648]

[0649] Example 35(cc) was prepared in a similar manner to that describedfor Example 35(a) except that propargylamine was used instead ofpropylamine (76%): ¹H NMR (300 MHz, CDCl₃) δ 8.56 (m, 1H), 7.96 (d, 1H,J=8.6 Hz), 7.81 (d, 1H, 16.4 Hz), 7.68 (dt, 1H, J=1.8, 7.8 Hz), 7.6 (m,1H), 7.52-7.45 (m, 3H), 7.3-7.23 (m, 3H), 7.16 (m, 2H), 4.10 (m, 2),2.20 (t, 1H. J=2.6 Hz). LCMS (100% area) Rt=3.36 min, (pos) [M+H]/zCalc'd 411.1, found 411.1. Analyzed with 0.2 H₂0, 0.17 DMF, 1.2dichloromethane, Calc'd, C (58.44), H (4.19), N (11.05), S (6.07).Found: C (58.18), H (4.11), N (10.98), S (6.05).

Example 35(dd):6-[2-(ethoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0650]

[0651] Example 35(dd) was prepared in a similar manner to that describedfor Example 35(a) except that ethoxyamine was used instead ofpropylamine: ¹H NMR (300 MHz, CDCl₃) δ 11.60 (s, 1H), 8.71 (d, 1H, J=7.9Hz), 8.30 (d, 1H, J=8.5 Hz), 8.05 (d, 1H, J=16.4 Hz), 7.91 (dt, 1H,J=1.7, 7.7 Hz), 7.76 (d, 1H, J=7.8 Hz), 7.67 (m, 2H), 7.56 (dd, 1H,J=1.8, 7.3 Hz), 7.52-7.36 (m, 3H), 7.28 (m, 2H)4.06 (q, 2H, j=7.0 Hz),1.31 (t, 2H, J=7.0 Hz); LCMS (100% area) Rt=3.28 min, (pos) [M+H]/zCalc'd 417.1, found 417.1. Analyzed with 0.2 H₂O Calc'd, C (65.53), H(4.98), N (13.05), S (7.48). Found: C (65.66), H (4.91), N (12.75), S(7.44).

Example 35(ee):6-[2-(2-Methyl-2-propenylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0652]

[0653] Example 35(ee) was prepared in a similar manner to that describedfor Example 35(a) except that 2-methylallylamine was used insteadpropylarnine: ¹H NMR (300 MHz, CDCl₃) δ 8.56 (m, 1H), 7.98 (d, 1H, J=8.5Hz), 7.81 (d, 1H, J=16.4 Hz), 7.69 (dt, 1H, J=1.7, 7.7 Hz), 7.60 (m,1H), 7.53-7.42 (m, 3H), 7.32-7.24 (m, 3H), 7.16 (m, 2H), 6.72 (m, 1H),4.89 (s, 1H), 4.81 (s, 1H), 3.90 (d, 2H, J=5.5 Hz), 1.71 (s, 3H). LCMS(100% area) Rt=3.37 min, (pos) [M+H]/z Calc'd 427.1, found 427.1.Analyzed with 0.7 H₂0, 0.1 dichloromethane Calc'd, C (67.35), H (5.31),N (12.52), S (7.16). Found: C (67.55), H (5.39), N (12.35), S (7.15).

Example 35(ff):6-[2-((3-Fluorobenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0654]

[0655] Example 35(ff) was prepared in a similar manner to that describedfor Example 35(a) except that 3-fluorobenzylamine was used insteadpropylamine: ¹H NMR (300 MHz, CDCl₃) δ 8.60 (m, 1H), 7.97 (d, 1H, J=8.5Hz), 7.86 (d, 1H, J=16.4 Hz), 7.70 (m, 2H), 7.51 (m, 2H), 7.33 (m, 4H),7.18 (m, 2H), 7.11 (dd, 1H, J=1.6, 8.5 Hz), 6.95 (m, 3H), 4.51 (d, 2H,J=5.7 Hz); LCMS (100% area) Rt=3.55 min, (pos) [M+H]/z Calc'd 481.1,found 481.1. Analyzed with 0.7 H₂0, 0.5 dichloromethane, Calc'd, C(63,91), H (4.40), N (10.46), S (5.99). Found: C (63.80), H (4.34), N(10.34), S (5.98).

Example 35(gg):6-[2-(2-(methylamino)ethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0656]

[0657] Example 35(gg) was prepared in a similar manner to that describedfor Example 35(a) except that N-methylethylenediamine was used insteadof propylamine: ¹H NMR (300 MHz, CDCl₃) δ 8.60 (m, 1H), 7.98 (d, 1H,J=8.5 Hz), 7.81 (d, 1H, J=16.4 Hz), 7.69 (dt, 1H, J=1.7, 7.7 Hz), 7.52(m, 1H), 7.50-7.40 (m, 3H), 7.30-7.20 (m, 3H), 7.16 (m, 2H), 3.45 (t,2H), 2.69 (t, 2H), 2.15 (bs, 3H); LCMS (100% area) Rt=3.16 min, (pos)[M+H]/z Calc'd 430.1, found 430.1. Analyzed with 0.2 H₂O, 0.6dichloromethane, 0.06 hex, Calc'd, C (61.28), H (5.24), N (14.31), S(6.55). Found: C (61.26), H (5.14), N (14.22), S (6.56).

Example 35(hh):6-[2-(2-(Thien-2-yl)ethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0658]

[0659] Example 35(hh) was prepared in a similar manner to that describedfor Example 35(a) except that 2-(2-aminoethyl)thiophene was used insteadpropylamine: ¹H NMR (300 MHz, CDCl₃) δ 8.56 (m, 1H), 7.98 (d, 1H, J=8.5Hz), 7.81 (d, 1H, J=16.4 Hz), 7.69 (dt, 1H, J=1.7, 7.7 Hz), 7.60 (m,1H), 7.53-7.42 (m, 3H), 7.32-7.24 (m, 3H), 7.16 (m, 2H), 6.72 (m, 1H),6.63 (m, 1H), 6.52 (m 1H), 3.45 (q, 2H), 3.00 (t, 2H). Analyzed with 0.5H₂O, 0.07 dichloromethane Calc'd, C (65.35), H (4.69), N (11.26), S(12.82). Found: C (65.49), H (4.80), N (11.21), S (12.77).

Example 35(ii):6-[2-(aminocarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0660]

[0661] Example 35(ii) was prepared in a similar manner to that describedfor Example 35(a) except that hydrazine was used instead propylamine: ¹HNMR (300 MHz, dmso-d6) □ 13.3 (s, 1H), 9.57 (s, 1H), 8.54 (d, 1H, J=3.9z), 8.14 (d, 1H, J=8.5 Hz), 7.89 (d, 1H, J=16.4 Hz), 7.73 (dt, 1H,J=1.7, 7.6 Hz), 7.60 (d, 1H, J=7.9 Hz), 7.50 (m, 2H), 7.40 (dd, 1H,J=1.8, 7.1 Hz), 7.3-7.1 (m, 4H), 7.0 (m, 1H). LCMS (100% area) Rt=0.55min, (pos) [M+H]/z Calc'd 388.1, found 388.1. Analyzed with 0.1 DMF,0.55 EtOAc, 0.12 Tol (NMR) and 0.15 H₂O Calc'd, C (63.98), H (5.15), N(15.63), S (7.02). Found: C (63.99), H (5.07), N (15.75), S (6.89).

[0662] Examples 35(jj)-35(nn) can be prepared in a similar manner tothat described for Example 35(a).

Example 35(jj)

[0663]

Example 35(kk)

[0664]

Example 35(ll)

[0665]

Example 35(mm)

[0666]

Example 35(nn)

[0667]

Example 36(a):6-[2-(N²-(1-Methylimidazol-2-ylmethylidene)hydrazino)carbonyl)henylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0668]

[0669] The compound prepared in Example 35(ii) (40 mg, 0.103 mmol) wastreated with 1-methyl-2-imidazolecarboxaldehyde (29 mg, 0.258 mmol, 2.5equiv) in ethanol to give Example 36(a): ¹H NMR (300 MHz, dmso-d6) δ8.60 (m, 2H), 8.31 (s, 1H), 8.18 (d, 1H), 8.02 (d, 1H), 7.98 (d, 1H),7.80 (m, 2H), 7.63 (m, 2H), 7.40 (m, 3H), 7.30 (m, 1H), 7.20 (m, 1H),7.02 (m, 2H), 6.93 (s, 1H), 4.00 (s, 3H); LCMS (100% area) Rt=4.0 min,(pos) [M+H]/z Calc'd 480.2, found 480.2. Analyzed with 1.45 H₂O Calc'd,C (61.76), H (4.76), N (19.39), S (6.34). Found: C (61.78), H (4.67), N(19.34), S (6.39).

Example 36(b):6-[2-(N²-(pyrid-2-ylmethylidene)hydrazino)carbonyl)-phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0670]

[0671] Example 36(b) prepared in a similar manner to that described forExample 36(a) except that 2-pyridylcarboxaldehyde was used instead of1-methyl-2-imidazolecarboxaldehyde: ¹H NMR (300 MHz, CDCl₃) δ 8.57 (m,2H), 8.45 (m, 2H), 8.22 (d, 1H), 8.10 (s, 1H), 7.93 (d, 1H), 7.83 (d,1H), 7.8-7.1 (m, 1H); LCMS (100% area) Rt=4.0 min, (pos) [M+H]/z Calc'd477.1, found 477.1. Analyzed with 0.85 H₂O Calc'd, C (65.93), H (4.45),N (17.09), S (6.52). Found: C (66.02), H (4.42), N (16.95), S (6.38).

Example 36(c):6-[2-(N²-(2,2,2-trifluroethylidene)hydrazino)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0672]

[0673] Example 36(c) was prepared in a similar manner to that describedfor Example 36(a) except that trifluoroacetaldehyde was used instead of1-methyl-2-imidazolecarboxaldehyde: ¹H NMR (300 MHz, dmso-d6) δ 8.70 (m,1H), 8.25 (m, 1H), 8.02 (d, 1H), 7.90 (dt, 1H), 7.80-7.20 (m, 10H). LCMS(100% area) Rt=5.64 min, (pos) [M+H]/z Calc'd 468.1, found 468.0.Analyzed with 0.75 H₂O Calc'd, C (57.39), H (3.67), N (14.56), S (6.67).Found: C (57.44), H (3.67), N (14.56), S (6.67).

Example 37(a):6-[6-Fluoro-2-(ethoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0674]

[0675] Example 37(a) was prepared in a similar manner to that describedfor Example 35(a) except that the starting material described below wasemployed and that ethoxyamine was used instead of propylamine: ¹H NMR(300 MHz, CDCl₃) δ 8.59 (m, 1H), 8.08 (d, 1H), 7.88 (d, 1H, J=16.4 Hz),7.79 (t, 1H), 7.65 (d, 1H), 7.60 (m, 1H), 7.50 (d, 1H, J=16.4 Hz), 7.40(t, 1H), 7.36 (d, 1H), 7.28 (s, 1H), 7.23 (m, 1H), 7.10 (d, 1H), 3.90(q, 2H), 1.19 (t, 3H). LCMS (100% area) Rt=4.85 min, (pos) [M+H]/zCalc'd 435.1, found 435.1, (neg) [M-H]/z Calc'd 433.1, found 433.1.Analyzed with 0.35 H₂O, 0.07 EtOAc Calc'd, C (62.56), H (4.57), N(12.54), S (7.17). Found: C (62.61), H (4.55), N (12.49), S (7.11).

[0676] Starting material was prepared as follows:

[0677] A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) inDMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0equiv) at 23° C. The mixture was stirred under argon for 10 h. Thesolution was diluted with ethyl acetate (50 mL) and water (50 mL) and10% citric acid (5 mL). The organic layer was washed with saturatedaqueous sodium bicarbonate, dried over sodium sulfate, decanted andconcentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoicacid ethyl ester: ¹H NMR (300 MHz, CDCl₃) δ 7.71 (t, 1H), 7.38 (m, H),7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min,(pos) [M+H]/z Calc'd 201.0, found 200.9.

[0678] The above thioether was prepared in a similar manner to thatdescribed for Example 33(a), step (iii) except that3-Fluoro-2-mercapto-benzoic acid ethyl ester was usedinsteadofthiosalicylate(320 mg,39%): FTIR (thin film) 2952, 1727, 1607,1586, 1564, 1469, 1433, 1366, 1292, 1249, 182, 1141, 1074, 836 cm−1; ¹HNMR (300 MHz, CDCl₃) δ 8.62 (m, 1H), 7.90 (d, 1H, J=8.6 Hz), 7.85 (d,1H, J=16.4 Hz), 7.67 (dt, 1H, J=1.8, 7.7 Hz), 7.57-7.38 (m, 5H),7.23-7.10 (m, 3H), 5.65 (s, 2H), 4.34 (q, 2H, J=7.1 Hz), 3.56 (t, 2H,J=8.2 Hz), 1.30 (t, 3H, J=7.1 Hz), 0.88 (t, 2H, J=8.2 Hz), −0.06 (s,9H); LCMS (100% area) Rt =4.44 min, (pos) [M+H]/z Calc'd 549.2, found549.2.

[0679] The carboxylic acid above was prepared in a similar manner tothat described for Example 33(a), step (iv) (303 mg, 99%): FTIR (thinfilm) 2953, 2496, 1715, 1643, 1607, 1567, 1470, 1434, 1300, 1250, 1221,1075, 967, 932, 836 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.81 (m, 1H), 7.87(m, 2H), 7.79 (m, 3H), 7.65 (m, 2H), 7.56 (m, 1H), 4.40 (m, 1H), 7.30(m, 1H), 7.00 (dd, 1H, J=1.4, 8.5 Hz), 5.58 (s, 2H), 3.59 (t, 2H, J=8.2Hz), 0.93 (t, 2H, J=8.2 Hz), -0.01 (s, 9H). LCMS (100% area) Rt=10.47min, (pos) [M+H]/z Calc'd 522.2, found 522.2.

[0680] The above salt was prepared in a similar manner to that describedfor Example 33(g): ¹H NMR (300 MHz, dmso-d6) δ 13.2 (s, 1H), 8.68 (m,1H), 8.12 (d, 1H, J=8.5 Hz), 7.98 (d, 1H, J J=16.4 Hz), 7.88 (dt, 1H,J=1.8, 7.6 Hz), 7.73 (d, 1H, J=7.9 Hz), 7.61 (d, 1H, J=16.4 Hz),7.43-7.32 (m, 3H), 7.20 (m, 2H), 7.07 (t, 1H), 3.23 (m, 8H), 1.68 (m,8H), 1.41 (m, 8H), 1.04 (t, 12H).

[0681] The above pentafluorophenyl ester was prepared in a similarmanner to that described for Example 35(a), step (i): LCMS (100% area)Rt=10.53 min, (pos) [M+H]/z Calc'd 558.1, found 558.1.

Example 37(b):6-[6-Fluoro-2-(cyclopropylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0682]

[0683] Example 37(b) was prepared in a similar manner to that describedfor Example 37(a) except that cyclopropylamine was used instead ofethoxyamine: ¹H NMR (300 MHz, dmso-d6) δ 8.42 (m, 1H), 8.28 (d, 1H),7.83 (d, 1H), 7.75 (m, 2H), 7.60 (m, 1H), 7.31 (m, 2H), 7.15 (m, 4H),6.86 (d, 1H), 2.58 (m, 1H), Q.42 (m, 2H), 0.23 (m, 2H). LCMS (100% area)Rt=4.91 min, (pos) [M+H]/z Calc'd 431.1, found 431.1, (neg) [M-H]/zCalc'd 429.1, found 429.2. Analyzed with 0.55 H₂O Calc'd, C (65.46), H(4.60), N (12.72), S (7.28). Found: C (65.52), H (4.58), N (12.64), S(7.06).

Example 37(c):6-6-fluoro-2-(isopropoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0684]

[0685] Example 37(c) was prepared in a similar manner to that describedfor Example 37(a) except that isopropoxyamine was used instead ofethoxyamine: ¹H NMR (300 MHz, CDCl₃) δ 9.50 (bs, 1H), 8.47 (m, 1H), 7.72(d, 1H), 7.68 (d, 1H, J=16.4 Hz), 7.54 (dt, 1H), 7.35 (m, 4H), 7.20 (m,4H), 4.03 (m, 1H), 1.07 (d, 6H); LCMS (100% area) Rt=4.90 min, (pos)[M+H]/z Calc'd 449.1, found 449.1. Analyzed with 0.1 DMF, 0.3 H₂OCalc'd, C (63.28), H (4.87), N (12.45), S (6.95). Found: C (63.22), H(4.84), N (12.37), S (6.91).

Example 37(d):⁶-[6-Fluoro-2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0686]

[0687] Example 37(d) was prepared in a similar manner to that describedfor Example 37(a) except that methylamine was used instead ofethoxyamine: ¹H NMR (300 MHz, dmso-d6) δ 8.37 (m, 1H), 8.18 (m, 1H),7.87 (d, 1H), 7.67 (d, 1H, J=16.4 Hz), 7.59 (dt, 1H), 7.40 (d, 1H), 7.30(m, 2H), 7.20 (m, 4H), 6.85 (d, 1H), 2.49 (d, 3H); LCMS (100% area)Rt=4.63 min, (pos) [M+H]/z Calc'd 405.1, found 405.2, (neg) [M-H]/zCalc'd 403.1, found 403.1. Analyzed with 0.2 DMF, 0.3 CH₂Cl₂ (nmr), 0.3H₂O Calc'd, C (61.13), H (4.39), N (13.07), S (7.13). Found: C (61.08),H (4.35), N (13.14), S (7.22).

Example 38(a):6-[2-(2-Methylquinol-6-ylcarbamoyl)phenylsulfanyl]-3-E-(2-styryl)-1H-indazole

[0688]

[0689] Example 38(a) was prepared in a similar manner to that describedfor Example 33(b) except that steps (i) and (ii) were omitted: ¹H NMR(300 MHz, CDCl₃) δ 8.58 (s, 1H), 8.13 (s, 1H), 7.80 (m, 3H), 7.67 (t,1H), 7.43 (m, 2H), 7.34-7.16 (m, 9H), 7.13 (d, 1H), 7.07 (d, 1H), 2.60(s, 3H). LCMS (100% area) Rt=3.87 min, (pos) [M+H]/z Calc'd 513.1, found513.2.

Example 38(b):6-[2-((4-piperizin-1-yl-3-trifluoromethylphenyl)carbamoyl)phenylsulfanyl]-3-E-(2-stryl)-1H-indazole

[0690]

[0691] Example 38(b) was prepared in a similar manner to that describedfor Example 38(a) except that3-trifluoromethyl-4-piperazin-1-yl-phenylamine was used instead of⁶-amino-2-methylquinoline: ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 7.95(d, 1H), 7.77 (m, 2H), 7.69 (s, 1H), 7.55 (m, 3H), 7.40-7.25 (m, 9H),7.20 (d, 1H), 3.00 (m, 4H), 2.83 (m, 4H). LCMS (100% area) Rt=3.94 min,(pos) [M+H]/z Calc'd 600.2, found 600.2. Analyzed with 0.1 hex (nmr),1.4 H₂O Calc'd, C (63.71), H (5.12), N (11.06), S (5.06). Found: C(63.67), H (5.06), N (10.98), S (5.00).

Example 39(a):6-[2-(Methylcarbamoyl)phenylamino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0692]

[0693] A solution ofN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzamide(39 mg, 0.07820 mmol) (synthesis described below), ethylene diamine (21μL, 0.3128 mmol), and 1M TBAF in THF (0.63 ml, 0.6256 mmol), was stirredin a 90° C. oil bath for 2 hr. The crude reaction mixture was dilutedwith ethyl acetate (50 mL), extracted 1M sodium bicarbonate solution(2×20 ml), brine (5×20 ml), dried magnesium sulfate, filtered, andconcentrated to a solid. The solid was dissolved in THF, concentrated toan oil, then triturated with CH₂Cl₂/Et₂O, causing precipitation of apowder. The powder was collected by filtration, rinsed with Et₂O, anddried under high vacuum. Mass of collected solid was 20 mg (70% yield).¹H NMR (DMSO-d₆) δ 12.91 (bs, 1H), 9.86 (s, 1H), 8.60 (d, J=4.0 Hz, 1H),8.52 (m, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.90 (d, J=16.4 Hz, 1H), 7.80 (dt,J=1.7, 7.5 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.51 (d, J=16.1 Hz, 1H),7.47-7.34 (m, 2H), 7.25 (m, 2H), 7.00 (d, J=9.6 Hz, 1H), 6.89 (t, J=7.0Hz, 1H), 2.79 (d,J=4.7 Hz, 3H). Anal. Calcd. for C₂₂H₁₉N₅.0.5 CH₂Cl₂: C,65.61; H, 4.89; N, 17.00. Found: C, 65.52; H, 5.08; N, 16.78.

[0694] The starting material was prepared as follows:

[0695] A solution of 191 mg (0.4 mmol) of6-iodo-3-carboxaldehyde-1-[2-(trimethyl-silanly)-ethoxymethyl]-1H-indazole(from Example 33(a), step(ii)), methyl anthranilate (120.1 mg, 0.8mmol), 2-(dicyclohexylphosphino) biphenyl (28 mg,0.08 mmol), Pd₂(dba)₃(18.4 mg, 0.02 mmol), K₃PO₄ (212.3 mg, 1.0 mmol), dissolved in dry DME(1.0 mL), was vacuum flushed with argon (3X), then stirred under anargon atmosphere for 3d in an oil bath at 80° C. The crude mixture wasfiltered through a plug of SiO₂ eluted with ethyl acetate, then purifiedby “chromatotron” radial chromatography eluted with 25% CH₃CN/CH₂Cl₂.The mass of the fractions that were pure was 42 mg. An addition 120 mgof product that was ˜90% pure was also collected. The total yield ofN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzamidewas 162 mg or ˜81%.

Example 39(b):6-[2-(Prop-2-ynylcarbamoyl)phenylamino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0696]

[0697] Example 39(b) was prepared in a similar manner to that describedfor Example 39(a) except that the propargylamine was used instead ofmethylamine. ¹H NMR (CDCl₃) δ 9.50 (s, 1H), 8.64 (d, J=4.5 Hz, 1H), 7.98(d, J=8.9 Hz, 1H), 7.90 (d, J=16.4 Hz, 1H), 7.70 (dt, J=1.7, 7.5 Hz,1H), 7.57 (d, J=16.3 Hz, 1H), 7.52-7.43 (m, 3H), 7.34 (dt, J=1.5, 7.2Hz, 1H), 7.26 (m, 3H), 7.34 (ddd, J=1.0, 4.9, 7.5 Hz, 1H), 7.09 (dd,J=1.7, 9.0 Hz, 1H), 6.85 (dt, J=1.0,7.0 Hz, 1H), 6.33 (bs, 1H), 4.24(dd, J=2.6,5.3 Hz, 2H), 2.30 (t, J=5.5 Hz, 1H). Anal. Calcd. forC₂₄H₁₉N₅O.0.25 CH₂Cl₂: C, 70.24; H, 4.74; N, 16.89. Found: C, 70.72; H,4.96; N, 16.55.

Example 40(a):6-(3-Amino-benzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0698]

[0699] Example 40(a) was prepared in a similar manner to that describedfor Example 11. ¹H NMR (300 MHz, DMSO-d₆) δ 13.5 (s, 1H), 8.62 (d, 1H,J=3.86 Hz), 8.34 (d, 1H, J=8.5 Hz), 8.01 (d, 1H, J=16.36 Hz), 7.87 (s,1H), 7.83 (td, 1H, J=7.69 Hz, J=1.81 Hz), 7.58-7.71 (m, 3H), 7.29 (qd,1H, J=7.39 Hz, J=0.98 Hz), 7.21 (t, 1H, J=7.77), 7.00 (t, 1H, J=1.86Hz), 6.90 (dt, 1H, J=6.15 Hz, J=1.40 Hz), 6.86 (m, 1H), 5.40 (bs, 2H).MS (ESI+) [M+H]/z Calc'd 446, found 446. Calc'd: C, 74.10; H, 4.74; N,16.46. Found: C, 72.72; H, 4.87; N, 16.02.

[0700] The staring material was prepared as follows:

[0701] To m-amino-phenyl boronic acid (8.22 g, 60 mmol) indimethyformamide (60 ml) at 23° C. under an atmosphere of argon wasadded triethylamine (10 ml, 72 mmol) and 4-(dimethylamino)pyridine(0.366 g, 3 mmol). The resulting solution was heated to 50° C. Carbonicacid 4-nitro-phenyl ester 2-trimethylsilanyl-ethyl ester (20.4 g, 72mmol) was added in 5 by 4 g portions over 18 hours. After 44 h carbonicacid 4-nitro-phenyl ester 2-trimethylsilanyl-ethyl ester (3.4 g, 12mmol) was added followed by triethylamine (1.7 ml, 12 mmol). After 63 hthe reaction mixture was concentrated to an oil. Purification by silicagel chromatography eluting with 3-7 to 7-3 ethyl acetate-hexane gave(3-boronic acid-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester(8.12 g, 48%): R_(f) sm 0.067, p 0.33 (ethyl acetate-hexane 1:1); ¹H NMR(300 MHz, CD₃OD) δ 7.64 (s, 1H), 7.49 (d, 1H, J=8.94 Hz), 7.26 (m, 2H),4.23 (t, 2H, J=8.28 Hz), 1.06 (t, 2H, J=8.21 Hz) 0.72 (s, 9H). MS (ESI)[M+Na]/z Calc'd 304, found 304.

[0702] A mixture of⁶-iodo-3-((E)-2-pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(7.1 g, 14.8 mmol), (3-boronic acid-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (8.32 g, 29.6 mmol),dichlorobis(triphenylphosphine)-palladium(II) (312 mg, 0.44 mmol),potassium carbonate (6.13 g, 44.4 mmol) and triethylamine (2.1 ml, 14.8)in anisole (60 ml) was heated to 80° C. under an atmosphere of carbonmonoxide. After 24 h more triethylamine (2.1 ml, 14.8 mmol) was added.After 33 hrs the reaction was determined to be complete by TLC analysis(ethyl acetate-hexane 7-3). The reaction mixture was cooled to 23° C.,then diluted with saturated NaHCO₃ (aq) (40 ml) and ethyl acetate (300ml). The phases were separated and the aqueous was extracted with ethylacetate (2×100 mls). The pooled ethyl acetate was washed with brine (100ml) and dried over Na₂SO₄, filtered and concentrated. Purification bysilica gel chromatography gave(3-{1-[3-(2-Pyridin-2-yl-ethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yl]-methanoyl}-phenyl)-carbamicacid 2-trimethylsilanyl-ethyl ester as a yellow glass (7.22 g, 79%). ¹HNMR (300 MHz, CDCl₃) δ 8.65 (d, 1H, J=3.93 Hz), 8.10 (d, 1H, J=8.54 Hz),8.04 (s, 1H), 7.94 (d, 1H, J=16.33 Hz), 7.82 (s, 1H), 7.66-7.77 (m, 3H),7.61 (d, 1H, J=16.35 Hz), 7.40-7.51 (m, 3H), 7.19 (m, 1H), 7.00 (s, 1H),5.77 (s, 2H), 4.25 (t, 2H, J=6.93 Hz), 3.60 (t, 2H, J=8.10 Hz), 1.04 (t,2H, J=6.79 Hz), 1.00 (t, 2H, J=8.13 Hz), 0.04 (s, 9H), 0.0 (s, 9H). MS(ESI+) [M+H]/z Calc'd 615, found 615.

Example 40(b): 6-(3-Aminomethyl-benzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0703]

[0704] Example 40(b) was prepared in a similar manner to that of Example40(a) except that in step (i) 4-methyl-3-amino-phenyl boronic acid,prepared as described below, was used in place of m-amino-phenyl boronicacid. ¹H NMR (DMSO-d₆) δ 13.6 (s, 1H), 8.62 (d, 1H, J=3.81 Hz), 8.33 (d,1H, J=8.47 Hz), 8.01 (d, 1H, J=16.36 Hz), 7.85 (s, 1H), 7.82 (dd, 1H,J=7.60 Hz, J=1.80 Hz), 7.70 (d, 1H, J=7.81 Hz), 7.63 (d, 1H, J=16.36Hz), 7.57 (dd, 1H, J=8.47 Hz, J=1.2 Hz), 7.29 (m, 1H), 7.12 (d, 1H,J=7.82 Hz), 7.09 (d, 1H, J=1.64 Hz), 6.90 (dd, 1H, J=7.59 Hz, J=1.65Hz), 5.16 (bs, 1H), 2.16 (s, 1H). MS (ESI+) [M+H]/z Calc'd 355, Anal.Calc'd: C, 74.56; H, 5.12; N, 15.81. Found: C, 73.86; H, 5.25; N, 15.34.

[0705] The starting material was prepared as follows:

[0706] A mixture of 4-methyl-3-nitro-phenyl boronic acid (3.34 g, 18.45mmol) and 10% Pd/C (334 mg) in MeOH (30 ml) was hydrogenated (1 atm.) at23° C. After 22 h the reaction mixture was filtered through celite andconcentrated to give 3-amino-4-methyl 10 phenyl boronic acid (2.53 g,91%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.21 (s, 1H), 7.08 (d, 1H, J=7.5 Hz),6.92 (d, 1H, J=7.46 Hz), 4.81 (bs, 2H), 2.09 (s, 3H). MS (ESI) [M+H]/zCalc'd 152, found 152.

Example 40(c):6-(5-Amino-2,4-dinethyl-benzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0707]

[0708] Example 40(c) was prepared in a similar manner to that of Example40(a) except that in step (i) 2,4-dimethyl-3-amino-phenyl boronic acid(prepared as described below) was used in place of m-amino-phenylboronic acid: ¹H NMR (DMSO-d₆) δ 8.62 (d, 1H, J=3.78 Hz), 8.32 (d, 1H,J=8.48 Hz), 7.99 (d, 1H, J=16.35 Hz), 7.83 (td, 1H, J=7.68 Hz, J=1.8Hz), 7.80 (s, 1H), 7.69 (d, 1H, J=7.80 Hz), 7.64 (dd, 1H, J=8.47 Hz,J=1.27 Hz), 7.62 (d, 1H, J=16.36 Hz), 7.29 (m, 1H), 6.94 (s, 1H), 6.64(s, 1H), 4.87 (bs, 2H), 2.12 (s, 3H), 2.10 (s, 3H). LCMS (ESI+) [M+H]/zCalc'd 369, found 369. Anal. Calc'd: C, 74.98; H, 5.47; N, 15.21. Found:C, 73.85; H, 5.56; N, 14.49.

[0709] The starting material was prepared as follows:

[0710] 2,4-Diemthylphenyl boronic acid was made in a similar manner asthat of Example 24(a), step (vii), except 2,4-dimethyl bromobenzene wasused as starting material. ¹H NMR (CD₃OD) δ 7.13 (d, 1H, J=7.43 Hz),7.00 (s, 1H), 6.97 (d, 1H, J=7.49 Hz), 2.28 (s, 3H), 2.28 (s, 3H). LCMS(ESI+) [M+H]/z Calc'd 151, found 151.

[0711] To fuming nitric acid (1 ml) cooled to -40° C. was added TFA (1ml). The resulting mixture was allowed to warm slightly to −35° C. and2,4-dimethyl phenyl boronic acid (150 mg, 1 mmol) was added in oneportion. After 1 h, ice was added and the heterogenous mixture wasfiltered. The resulting solid was suspended in Et₂O and extracted with3N NaOH (aq) (1 ml) then water (2 ml). The aqueous phase was acidifiedwith 3N HCl (aq) (1 ml) and back extracted with EtOAc (3×5 ml). Thepooled organics were washed with brine, dried with Na₂SO₄ decanted andconcentrated to give 2,4-dimethyl-5-nitro-phenyl boronic acid (93 mg,47%). LCMS (ESI+) [M+H]/z Calc'd 196, found 196.

[0712] 3-Amino4,6-dimethylphenyl boronic acid was prepared in a similaras that described for Example 40(b), step (i). ¹H NMR (CD₃OD) δ 6.83 (s,2H), 6.64 (s, 1H), 2.17 (s, 3H), 2.13 (s, 3H).

Example 41(a):⁶-[³-((l-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0713]

[0714] To a solution of ²-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid(323 mg, 2.1 mmol, 2.1 equiv.) in DMF (5 ml) at 23° C. under argon wasadded diisopropylethylamine (365 μl, 2.1 mmol, 2.1 equiv.), HATU (798mg, 2.1 mmol, 2.1 equiv.) and DMAP (cat.). To the resulting solution wasadded 6-(3-Amino-benzoyl)-3-E-(2-pyridin-2-yl)ethenyl)-1H-indazol(Example 40(a), 340 mg, 1 mmol, 1 equiv.). The reaction was followed byHPLC until all the starting analine was consumed -2 h (this gave amixture of mono and bis acylated compounds). The reaction mixture wasquenched with saturated NaHCO₃, then diluted with water and extractedwith ethylacetate. The pooled EtOAc was washed with water, brine, driedwith Na₂SO₄, filtered and concentrated to an oil. The oil was dissolvedin methanol (10 ml), K₂CO₃ (290 mg, 2.1 mmol, 2.1 equiv.) was added andthe resulting mixture was stirred at 23° C. until the bis-acylatedcompound was consumed (˜30 min.). The reaction mixture was concentratedto an oil, then partitioned between water and EtOAc. The organic phasewas washed with brine, dried with Na₂SO₄, filtered and concentrated.Purification by silica gel chromatography (1:1-8:2ethylacetate-dichloromethane) gave Example 41(a). ¹H NMR (300 MHz,DMSO-d₆) δ 13.6 (s, 1H), 10.3 (s, 1H), 8.62 (d, 1H, J=3.88 Hz), 8.38 (d,1H, J=8.51 Hz), 8.20 (s, 1H), 8.12 (td, 1H, J=7.58 Hz, J=1.78 Hz), 8.02(d, 1H, J=16.36 Hz), 7.93 (s, 1H), 7.83 (td, 1H, J=7.61 Hz, J=1.7 Hz),7.70 (d, 1H, J=7.78 Hz), 7.65 (d, 1H, J=16.23 Hz), 7.65-7.53 (m, 3H),7.30 (m, 1H), 4.43 (q, 2H, J=7.07 Hz), 2.21 (s, 3H), 1.31 (t, 3H, J=7.07Hz). MS (ESI+) [M+H]/z Calc'd 477, found 477. Anal. Calc'd: C, 70.57; H,5.08; N, 7.64. Found: C, 70.46; H, 5.11; N, 17.61.

Example 41(b): 6-[3-(pyridinylcarboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0715]

[0716] Example 41 (b) was prepared in a similar manner to that describedfor Example 41 (a), except that isonicotinic acid was used instead of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300 MHz, CD₃OD)δ 8.74 (d, 2H, J=6.04 Hz), 8.56 (d, 1H, J=4.14 Hz), 8.27 (m, 2H), 8.05(dt, 1H, J=7.97 Hz, J=1.64 Hz), 8.02 (s, 1H), 7.95 (d, 1H, J=16.55 Hz),7.83-7.91 (m, 3H), 7.73 (m, 2H), 7.56-7.67 (m, 3H), 7.32 (m, 1H). MS(ESI+) [M+H]/z Calc'd 446, found 446. Anal. Calc'd: C, 72.80; H, 4.30;N, 15.72. Found: C, 71.59; H, 4.43; N, 15.33.

Example 41(c):6-(3-crotonylamidobenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0717]

[0718] Example 41(c) was prepared in a similar manner to that describedfor Example 41(a), except that crotonic acid was used instead of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300 MHz,DMSO-d₆) δ 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, J=3.81 Hz), 8.37 (d,1H, J=8.49 Hz), 8.12 (s, 1H), 8.02 (d, 1H, J=16.34 Hz), 7.99 (d, 1H,J=7.88 Hz), 7.83 (td, 1H, J=7.67 Hz, J=1.78 Hz), 7.70 (d, 1H,J=7.85 Hz),7.65 (d, 1H, J=16.40 Hz), 7.63 (dd, 1H, J=8.43 Hz, J=1.23 Hz), 7.47-7.56(m, 2H), 7.29 (qd, 1H, J=7.39 Hz, J=0.99 Hz), 6.82 (m, 1H, J=6.9 Hz),6.11 (dd, J=15.21 Hz, J=1.68 Hz), 1.87 (d, 3H, J=6.89 Hz). MS (ESI+)[M+H]/z Calc'd 409, found 409. Anal. Calc'd: C, 73.51; H, 4.94; N,13.72. Found: C, 72.15; H, 4.97; N, 13.39.

Example 41(d):⁶-[³-(indol-4-ylcarboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0719]

[0720] Example 41(d) was prepared in a similar manner to that describedfor Example 41(a), except that 1H-Indole4-carboxylic acid was usedinstead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LCMS (ESI+)[M+H]/z Calc'd 484, found 484.

Example 41(e):6-[3-((5-acetylthien-2-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0721]

[0722] Example 41(e) was prepared in a similar manner to that describedfor Example 41(a), except that 5-acetyl-thiophene-2-carboxylic acid wasused instead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR(300 MHz, DMSO-d₆) δ 13.6 (s, 1H), 10.6 (s, 1H), 8.63 (d, 1H, J=3.83Hz), 8.39 (d, 1H, J=8.51 Hz), 8.20 (s, 1H), 8.14 (dt, 1H, J=7.25 Hz,J=2.05 Hz), 8.07 (d, 1H, J=4.09 Hz), 8.02 (d, 1H, J=16.42 Hz), 8.00 (d,1H, J=4.01 Hz), 7.94 (s, 1H), 7.83 (td, 1H, J=7.69 Hz, J=1.78 Hz),7.59-7.65 (m, 5H), 7.30 (qd, 1H, J=7.40 Hz, J=0.96 Hz), 2.58 (s, 3H). MS(ESI+) [M+H]/z Calc'd 493, found 493. Anal. Calc'd: C, 68.28; H, 4.09;N, 11.37; S, 6.51. Found: C, 66.07; H, 4.34; N, 10.91; S, 6.14.

Example 41(f):6-[3-(3,5-difluorophenylacetamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0723]

[0724] Example 41(f) was prepared in a similar manner to that describedfor Example 41(a), except that (3,5-difluoro-phenyl)-acetic acid wasused instead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR(300 MHz, DMSO-d₆) δ 13.6 (bs, 1H), 10.5 (s, 1H), 8.62 (d, 1H, J=4.02Hz), 8.36 (d, 1H, J=8.51 Hz), 8.05 (s, 1H), 8.01 (d, 1H, J=16.38 Hz),7.93 (d, 1H, J=7.88 Hz), 7.90 (s, 1H), 7.83 (td, 1H, J=7.61 Hz, J=1.77Hz), 7.70 (d, 1H, J=7.85 Hz), 7.64 (d, 1H, J=16.33 Hz), 7.61 (dd, 1H,J=8.45 Hz, J=1.15 Hz), 7.48-7.57 (m, 2H), 7.15-7.31 (m, 5H), 3.77 (s,2H). MS (ESI+) [M+H]/z Calc'd 495, found 495.

Example 41(g):6-[3-((5-methyl-1H-pyrazol-3-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0725]

[0726] Example 41(g) was prepared in a similar manner to that describedfor Example 41(a), except that 5-methyl-2H-pyrazole-3-carboxylic acidwas used in place of ²-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹HNMR (300 MHz, DMSO-d₆) δ 13.6 (bs, 1H), 13.0 (bs, 1H), 10.3 (bs, 1H),8.63 (d, 1H, J=3.95 Hz), 8.37 (d, 1H, J=8.66 Hz), 8.36 (s, 1H), 8.16 (d,1H, J=7.55 Hz), 8.02 (d, 1H, J=16.37 Hz), 7.93 (s, 1H), 7.83 (dt, 1H,J=7.61 Hz, J=1.73 Hz), 7.70 (d, 1H, J=7.82 Hz), 7.65 (d, 1H, J=16.36Hz), 7.65 (dd, 1H, J=8.55 Hz, J=1.12 Hz), 7.52 (m, 2H), 7.29 (m, 1H),6.50 (s, 1H), 2.29 (s, 3H). MS (ESI+) [M+H]/z Calc'd 449, found 449.Anal. Calc'd: C, 69.63; H, 4.49; N, 18.74. Found: C, 68.53; H, 4.95; N,17.47.

Example 41(h):6-[3-((2-RS-trans-methylcyclopropyl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0727]

[0728] Example 41(h) was prepared in a similar manner to that describedfor Example 41(a), except that 2-Methyl-cyclopropanecarboxylic acid wasused in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. R_(f)sm 0.32, Rfp 0.42 (ethyl acetate-dichloromethane 8:2). ¹H NMR (300 MHz,DMSO-d₆) δ 13.6 (s, 1H), 10.4 (s, 1H), 8.62 (dd, 1H, J=4.75 Hz, J=0.96Hz), 8.36 (d, 1H, J=8.47 Hz), 8.06 (t, 1H, J=1.67 Hz), 8.01 (d, 1H,J=16.37 Hz), 7.90 (m, 2H), 7.83 (td, 1H, J=7.68 Hz, J=1.79 Hz), 7.70 (d,1H, J=7.84 Hz), 7.64 (d, 1H, J=16.35 Hz), 7.61 (dd, 1H, J=8.47 Hz,J=1.32 Hz), 7.51 (t, 1H, J=7.69 Hz), 7.45 (dt, 1H, J=7.68 Hz, J=1.50Hz), 7.29 (dq, 1H, J=7.41 Hz, J=1.04 Hz), 1.51 (m, 1H), 1.23 (m, 1H),1.09 (d, 3H, J=5.93), 1.01 (m, 1H), 0.65 (m, 1H). MS (ESI+) [M+H]/zCalc'd 423, found 423. Anal. Calc'd: C, 73.92; H, 5.25; N, 13.26. Found:C, 71.41; H, 5.56; N, 13.27.

Example 41(i):6-[3-((1,5-dimethyl-1H-pyrazol-3-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0729]

[0730] Example 41(i) was prepared in a similar manner to that describedfor Example 41(a), except that 1,5-dimethyl-1H-pyrazole-3-carboxylicacid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylicacid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d,1H, J=3.87 Hz), 8.37 (d, 1H, J=8.49 Hz), 8.34 (d, 1H, J=1.63 Hz), 8.16(td, 1H, J=7.43 Hz, J=1.96 Hz), 8.02 (d, 1H, J=16.35 Hz), 7.92 (s, 1H),7.83 (dt, 1H, J=7.68 Hz, J=1.79 Hz), 7.70 (d, 1H, J=7.84 Hz), 7.65 (d,1H, J=16.35 Hz), 7.65 (dd, 1H, J=8.52 Hz, J=1.2 Hz), 7.52 (m, 2H), 7.29(m, 1H), 6.55 (s, 1H), 3.83 (s, 3H), 2.30 (s, 3H). MS (ESI+) [M+H]/zCalc'd 463, found 463. Anal. Calc'd: C, 70.12; H, 4.79; N, 18.17. Found:C, 69.59; H, 4.88; N, 17.86.

Example 41(j):6-[3-((3-methylpyridin-4-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0731]

[0732] Example 41(j) was prepared in a similar manner to that describedfor Example 41(a), except that 3-methyl-isonicotinic acid was used inplace of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300MHz, DMSO-d₆) δ 13.6 (s, 1H), 10.7 (s, 1H), 8.62 (dd, 1H, J=4.72 Hz,J=0.86 Hz), 8.57 (s, 1H), 8.55 (d, 1H, J=4.91 Hz), 8.37 (d, 1H, J=8.46Hz), 8.20 (s, 1H), 8.07 (dt, 1H, J=7.27 Hz, J=1.99 Hz), 8.02 (d, 1H,J=16.37 Hz), 7.93 (s, 1H), 7.83 (td, 1H, J=7.69 Hz, J=1.79 Hz), 7.70 (d,1H, J=7.84 Hz), 7.64 (d, 1H, J=16.27 Hz), 7.55-7.65 (m, 3H), 7.48 (d,1H, J=4.89 Hz), 7.30 (qd, 1H, J=7.39 Hz, J=1.02 Hz), 2.38 (s, 3H). MS(ESI+) [M+H]/z Calc'd 460, found 460.

Example 41(k):6-[3-(cydopropylcarboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0733]

[0734] Example 41(l) was prepared in similar manner as Example 41(a)except that cyclopropane carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (CDCl₃/MeOD) δ8.52 (d, 1H, J=3.9 Hz), 8.09 (d, 1H, J=8.5 Hz), 7.93 (s, 1H), 7.85-7.80(m, 3H), 7.71-7.63 (m, 2H), 7.55-7.48 (m, 3H), 7.39 (1H, t, J=7.8 Hz),7.16 (1H, qd, J=6.3, 1.5 Hz), 1.62-1.57 (m, 1H), 1.25-1.84 (m, 2H),0.87-0.81 (m, 2H). HRMS (MALDI) C₂₅H₂oN₄O₂ [M +H+]/z Calc'd 409.1659,found 409.1660.

Example 41(l):⁶-[³-((²-RS-trans-phenylcyclopropyl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0735]

[0736] Example 41 (l) was prepared in similar manner as Example 41 (a)except that (1S,2S)-²-phenyl-cyclopropanecarboxylic acid used in placeof 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (CDCl₃/MeOD) δ8.60 (d, 1H, J=4.2 Hz), 8.17 (d, 1H, J=8.4 Hz), 8.02 (s, 1H), 7.91 (t,3H, J=8.1 Hz), 7.78-7.71 (m, 2H), 7.63-7.56 (m, 3H), 7.47 (t, 1H),7.32-7.12 (m, 5H), 2.60-2.54 (m, 1H), 1.94-1.90 (m, 1H), 1.69 (q, 1H,J=4.8 Hz), 1.37-1.32 (m, 1H). HRMS C₃₁H₂4N402 Calc'd (M +H+)/z 485.1993,found 485.1995.

Example 41(m):6-[3-((3-methylisoxazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0737]

[0738] Example 41(m) was prepared in similar manner as Example 41(a)except that 3-methyl-isoxazole-5-carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 10.95(1H, s), 8.68 (1H, d, J=4.2 Hz), 8.44 (d, 1H, J=8.7 Hz), 8.35 (s, 1H),8.21-8.18 (m, 1H,), 8.08 (d, 1H, J=16.2 Hz), 7.98 (s, 1H), 7.87 (td, 1H,J=7.5, 1.8 Hz), 7.76-7.64 (m, 6H), 7.37-7.33 (m, 1H), 6.72 (s, 1H) 3.36(s, 3H). HRMS (MALDI) C₂6Hl₉N₅O₃ [M +H⁺]/z: Calc'd 450.1561, found450.1570.

Example 41(n):6-[3-((3-t-butyl-1-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0739]

[0740] Example 41(n) was prepared in similar manner as Example 41(a)except that 5-ten-butyl-2-methyl-2H-pyrazole-3-carboxylic acid used inplace of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR(CDCl₃/MeOD) δ 8.59 (d, 1H, J=4.8 Hz), 8.14 (d, 1H, J=8.4 Hz), 8.08-8.04(m, 1H,), 7.98-7.92 (m, 3H), .7.75 (td, 1H, J=7.8, 1.8 Hz), 7.68 (dd,1H, J=8.4 Hz), 7.61-7.56 (m, 3H), 7.52 (t, 1H, J=8.70 Hz), 7.25-7.21 (m,1H,), 6.75 (s, 1H,), 4.12 (s, 3H), 1.30 (s, 9H). HRMS (MALDI) C₃₀H₂₈N₆O₂[M⁺H+]/z: Calc. 505.2347, found 505.2353.

Example 41(o):6-[3-((5-chlorothien-2-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0741]

[0742] Example 41(o) was prepared in similar manner as Example 41(a)except that 5-chloro-thiophene-2-carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 10.58(s, 1H,), 8.68 (d, 1H, J=4.2 Hz), 8.43 (d, 1H, J=8.5 Hz), 8.22 (s, 1H,),8.15 (dt, I1H, J=7.5, 2.0 Hz), 8.08 (d, 1H, J=16.4 Hz), 8.00-7.98 (m,3H), 7.88 (td, 1H, J=7.7, 1.9 Hz), 7.78-7.62 (m, 4H,), 7.33 (d, 2H,J=4.1 Hz). HRMS (MALDI) C₂₆H₁₇N₄O₂CIS [M +H⁺]/z: Calc. 485.0843, found485.0853.

Example 41(p):6-[3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0743]

[0744] Example 41(p) was prepared in similar manner as Example 41(a)except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R_(t) 3.90 min(100% area). ¹H NMR (CDCL₃) δ 8.52 (d, 1H, J=4.8 Hz), 8.10 (d, 1H, J=8.4Hz), 7.98 (d, 1H, J=8.1 Hz), 7.93 (s, 1H,), 7.88-7.80 (m, 3H), 7.71-7.62(m, 2H), 7.56-7.49 (m, 4H), 7.44 (t, 1H, J=7.8 Hz), 7.16 (dd, 1H, J=7.1,4.8 Hz). HRMS (MALDI) C₂₇H₂₂N₆₀O₂. [M+⁺]/z: Calc. 463.1877, found465.1889.

Example 41(q):6-[3-((2-chloro-6-methylpyridin-4-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0745]

[0746] Example 41(q) was prepared in similar manner as Example 41(a)except that 2-chloro-6-methyl-isonicotinic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R_(t) 4.11 min.(100% area). ¹H NMR (DMSO-d₆) δ 10.77 (s, 1H), 8.68 (d, 1H, J=3.9 Hz),8.44 (d, 1H, J=8.4 Hz), 8.28 (s, 1H), 8.21 (dt, 1H, J=6.9, 2.1 Hz), 8.08(d, 1H, J=16.2 Hz), 7.98 (s, 1H), 7.92-7.64 (m, 9H), 7.35 (dd, 1H,J=6.6,4.8 Hz), 2.61 (s, 3H).

Example 41(r):6-[3-((1-n-propyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0747]

[0748] Example 41(r) was prepared in similar manner as Example 41(a)except that 5-methyl-2-propyl-2H-pyrazole-3-carboxylic acid used inplace of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR(DMSO-d₆) δ 10.29 (s, 1H), 8.58 (d, 1H, J=3.9 Hz), 8.33 (d, 1H, J=8.4Hz), 8.13 (s, 1H), 8.10 (dt, 1H, J=5.4, 2.1 Hz), 7.96 (d, 1H, J=16.5Hz), 7.87 (s, 1H), 7.78 (td, 1H, J=7.5, 1.5 Hz), 7.61-7.49 (m, 6H), 7.24(dd, 1H, J=6.9, 1.8 Hz), 4.32 (t, 2H, J=6.90 Hz), 1.69 (q, 2H, J =7.2Hz), 0.77 (t, 3H, 7.5 Hz). HRMS (MALDI) C₂₈H₂₀CIN₅O₂. [M+H⁺]/z: Calc.491.2190, found 491.2203.

Example 41(s):6-[3-(4-t-butylbenzamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0749]

[0750] Example 41(s) was prepared in similar manner as Example 41(a)except that 4-tert-butyl-benzoic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R_(t) 4.67 min.(100% area). ¹H NMR (DMSO) δ 10.45 (s, 1H), 8.44 (d, 1H, J=8.4 Hz), 8.32(s, 1H), 8.22 (d, 1H, J=7.5 Hz), 8.07 (d, 1H, J=1.6.5 Hz), 7.99-7.95 (m, 3H), 7.88 (td, 1H, J=7.7, 1.5 Hz), 7.69-7.59 (m, 7H), 7.38 (dd, 1H,13.5,5. 1 Hz), 1.36 (s, 9H). cl Example 41(t):6-[3-((1-Allyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0751] Example 41(t) was prepared in similar manner as Example 41(a)except that 2-allyl-5-methyl-2H-pyrazole-3-carboxylic acid used in placeof 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R_(t) 4.11 min.(100% area). ¹H NMR (DMSO) δ 10.46 (s, 1H), 8.74 (t, 1H, J=5.1 Hz), 8.48(d, 1H, J=8.4 Hz), 8.28 (s, 1H), 8.22 (t, 1H, J=5.4, 2.1 Hz), 8.15-8.01(m, 3H), 7.39 (td, 1H, J=7.8, 1.8 Hz), 7.82-7.63 (m, 6H) 7.39 (td, 1H,J=7.7,1.5 Hz), 6.14-6.02 (m, 1H), 5.22-5.03 (m, 4H), 2.38 (s, 3H). HRMS(MALDI) C₂₉H₂₄N₆O₂ (M+H⁺)/z: Calc. 489.2034, found 489.2035.

Example 41(u):6-[3-((2-chloro-6-methoxypyridin-4-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0752]

[0753] Example 41(u) was prepared in similar manner as Example 41(a)except that ²-chloro-6-methoxy-isonicotinic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC R_(t): 4.37 min.(100% area). ¹H NMR (DMSO-d₆) δ 10.74 (s, 1H), 8.68 (d, 1H, J=3.6 Hz),8.44 (d, 1H, J=8.4 Hz), 8.28 (s, 1H), 8.20 (td, 1H, J=6.6, 2.4 Hz), 8.07(d, 1H, J=16.2 Hz), 7.98 (s, 1H), 7.89 (td, 1H, J=7.7, 1.8 Hz),7.77-7.62 (m, 6H), 7.38 (s, 1H), 7.35 (dd, 1H, J=6.9, 1.8 Hz), 3.98 (s,3H).

Example 41(v):6-[3-((3-Ethyl-1-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0754]

[0755] Example 41(v) was prepared in similar manner as Example 41(a)except that 5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid used in placeof 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. R_(t) 4.16 min. (100%area). ¹H NMR (DMSO-d₆) δ 10.44 (s, 1H), 8.73 (d, 1H, J=3.0 Hz), 8.78(d, 1H, 8.7 Hz), 8.30 (s, 1H), 8.23 (d, 1H, J=6.9 Hz), 8.14-8.03 (m,2H), 7.93 (t, 1H, 6.9 Hz), 7.82-7.63 (m, 6H), 7.40 (t, 1H, J=6.3 Hz),7.01 (s, 1H), 4.12 (s, 1H), 2.68 (q, 2H, 7.8 Hz), 1.30 (t, 3H, J=7.5Hz). HRMS (MALDI) C₂₈H₂₄N₆O₂ [M+H⁺]/z: Calc. 477.2034, found 477.2054.

Example 41(w):⁶-[3-((2-chloropyridin-4-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0756]

[0757] Example 41(w) was prepared in similar manner as Example 41(a)except that 2-chloro-isonicotinic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC R_(t): 3.99 min.(100% area). ¹H NMR (DMSO-d₆) δ 10.88 (s, 1H), 7.33 (d, 2H, J=4.8 Hz),8.49 (d, 1H, J=8.4 Hz), 8.33 (s, 1H), 8.26 (td, 1H, J=6.9, 3.0 Hz),8.12-7.91 (m, 5H), 7.82-7.63 (m, 5H), 7.40 (t, 1H, J=4.8 Hz).

Example 41(x):6-[3-((1-Isopropyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0758]

[0759] Example 41(x) was prepared in similar manner as Example 41(a)except that 2-isopropyl-5-methyl-2H-pyrazole-3-carboxylic acid used inplace of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R_(t)4.19 min. (100% area). ¹H NMR (DMSO) δ 10.46 (s, 1H), 8.72 (t, 1H,J=4.80 Hz), 8.48 (d, 1H, J=9.0 Hz), 8.31 (s. 1H), 8.21 (td, 1H, J=9.6,2.1 Hz), 8.15-7.98 (m, 2H), 7.96-7.84 (m, 1H), 7.82-7.65 (m, 5H),7.42-7.38 (m, 1H), 6.88 (s, 1H), 5.64-5.38 (m, 1H), 2.32 (s, 3H), 1.48(d, 1H, J=6.6 Hz). HRMS (MALDI) C₂₉H₂6N₆O₂ [M+⁺]/z; Calc. 491.2190,found 491.2194.

Example 41(y):6-[3-(isopropoxycarbonylamino)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0760]

[0761] Example 41(y) was prepared in similar manner as Example 41(a)except that isopropyl chloroformate was used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 9.97(s, 1H), 8.72 (t, 2H, J=4.8 Hz), 8.47 (d, 1H, J=8.7 Hz), 8.34-7.96 (m,3H), 8.01-7.87 (m, 2H), 7.82-7.69 (m, 2H), 7.52 (dt, 1H, J=7.5, 1.2 Hz),7.42-7.36 (m, 2H), 3.68 (d, 2H, J=6.6 Hz), 2.02 (m, 1H), 1.02 (d, 6H,J=6.6 Hz). HRMS (MALDI) C₂₆H₂₄O₄ ₃ [M+H⁺]/z: Calc' 441.1921, found441.1937.

Example41(z):6-[3-((4-chloropyridin-2-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0762]

[0763] Example 41(z) was prepared in similar manner as Example 41(a)except that used 4-chloro-pyridine-2-carboxylic acid was used in placeof 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC R_(t): 4.40 min.(100% area). ¹H NMR (DMSO-₆) δ 10.99 (s, 1H), 8.72 (d, 1H, J=5.4 Hz),8.63 (d, 1H, J=3.9 Hz), 8.44 (s, 1H), 8.38 (d, 1H, J=8.4 Hz), 8.25 (dt,1H, J=6.6, 2.4 Hz), 8.16 (d, 1H, J=1.8 Hz), 8.02 (d, 1H, J=16.2 Hz),7.94 (s, 1H), 7.86-7.80 (m, 2H), 7.72-7.58 (m, 5H), 7.29 (dd, 1H, J=6.9,6.0 Hz).

Example 41(aa):6-[3-(pyridin-2-ylcarboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0764]

[0765] Example 41(aa) was prepared in a similar manner to that describedfor Example 41(a), except that pyridine-2-carboxylic acid was usedinstead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300MHz, DMF-d₆) δ 10.9 (s, 1H), 8.74 (m, 1H), 8.63 (dd, 1H, J=4.78 Hz, 0.94Hz), 8.46 (s, 1H), 8.38 (d, 1H, J=8.48 Hz), 8.25 (dt, 1H, J=7.17 Hz,J=2.05 Hz), 8.16 (dt, 1H, J=7.73-Hz, J=1.04 Hz), 8.07 (td, 1H, J=7.56Hz, J=1.67 Hz), 8.02 (d, 1H, J=16.28 Hz), 7.95 (s, 1H), 7.83 (td, 1H,J=7.65 Hz, J=1.81 Hz), 7.22-7.66 (m, 4H), 7.30 (qd, 1H, J=7.40 Hz,J=1.02 Hz). MS (ESI+) [M+H]/z Calc'd 446, found 446.

Example 41(bb):6-[3-(3-methoxybenzamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0766]

[0767] Example 41 (bb) was prepared in similar manner as Example 41(a)except that ³-methoxy-benzoic acid used in place of2-ethyl-S-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 10.50(s, 1H,), 8.67 (d, 1H, J=3.9 Hz), 8.46 (d, 1H, I=8.7 Hz), 8.33 (s, 1H),8.22 (dt, 1H, J=7.8, 1.8), 8.08 (d, 1H, J=15.0 Hz), 8.00 (s, 1H,),7.78-7.54 (m, 8H), 7.51 (t, 1H, 7.8 Hz), 7.38-7.33 (m, 1H), 7.23 (dd,1H, J=7.5, 1.5 Hz), 3.90 (s, 3H). HRMS (MALDI) C₂₉H₂₂N₄O₃. [M+H⁺]/z:Calc. 475.1765, found 475.1763.

Example 41(cc):6-[3-(phenoxyamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0768]

[0769] Example 41 (cc) was prepared in a similar manner to thatdescribed for Example 41(a), except that phenyl chloroformate was usedinstead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. mp 212-217°C., ¹H NMR (300 MHz, DMSO-d₆) δ 8 13.63 (s, 1H), 10.51 (s, 1H), 8.62 (d,1H, J=4.3 Hz), 8.36 (d, 1H, J=8.6 Hz), 10 8.04-7.81 (m, 5H), 7.71-7.40(m, 7H), 7.31-7.22 (m, 4H). ESIMS m/z 461 [M+H]⁺. Anal. calc'd forC₂₈H₂₀N₄O₃×0.3 H₂O (465.9 g mol⁻¹): C, 72.18; H, 4.46; N, 11.33. Found:C, 72.41; H, 4.63; N, 11.57.

Example 41(dd):6-[3-(3,3-methylacrylamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0770]

[0771] Example 41(dd) was prepared in a similar manner to that describedfor Example 41(a), except that 3,3-dimethylacrylic acid was used insteadof 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300 MHz,DMSO-d₆) δ 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, J=3.81 Hz), 8.37 (d,1H, J=8.49 Hz), 8.12 (s, 1H), 8.02 (d, 1H, J=16.34 Hz), 7.99 (d, 1H,J=7.88 Hz), 7.83 (td, 1H, J=7.67 Hz, J 1.78 Hz), 7.70 (d, 1H, J=7.85Hz), 7.63 (dd, 1H, J=8.43 Hz, J=1.23 Hz), 7.47-7.56 (m, 2H), 7.29 (qd,1H, J=7.39 Hz, J=0.99 Hz), 6.82 (m, 1H, J=6.9 Hz), 5.85 (s, 1H), 2.12(s, 3H), 1.85 (s, 3H). MS (ESI+) [M+H]/z Calc'd 409, found 409. Anal.Calc'd for C₂₆H₂₂N₄O₂×0.33 TBME: C, 73.54; H, 5.80; N, 12.41. Found: C,73.26; H, 5.76; N, 12.36.

Example 41(ee):6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxaniido)4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0772]

[0773] Example 41(ee) was prepared in similar manner as Example 41(a)except that Example 40(b) was used in place of Example 40(a). ¹H NMR(DMSO-d₆) δ 13.6 (s, 1H), 9.94 (s, 1H), 8.62 (d, 1H, J=3.8 Hz), 8.36 (d,1H, J=8.51 Hz), 8.01 (d, 1H, J=16.36 Hz), 7.91 (s, 1H), 7.84 (dd, 1H,J=7.66 Hz, J=1.74 Hz), 7.81 (s, 1H), 7.70 (d, 1H, J=7.9 Hz), 7.64 (d,1H, J=16.45 Hz), 7.62 (m, 2H), 7.50 (d, 1H, J=7.83 Hz), 7.29 (m, 1H),6.82 (s, 1H), 4.42 (q, 2H, J=7.06 Hz), 2.36 (s, 3H), 2.21 (s, 3H), 1.30(t, 3H, J=7.09 Hz). MS (ESI+) [M+H]/z Calc'd 491, found 491. Anal.Calc'd: C, 71.00; H, 5.34; N, 17.13. Found: C, 70.80; H, 5.38; N, 17.00.

Example 41(ff):6-[3-((1-Allyl-3-methyl-1H-pyrazol-5-yl)carboxamido)-4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0774]

[0775] Example 41(ff) was prepared in a similar manner to that describedfor Example 41(ee), except that2-allyl-5-methyl-2H-pyrazole-3-carboxylic acid was used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 13.6(s, 1H), 9.98 (s, 1H), 8.62 (d, 1H, J=4.60 Hz), 8.36 (d, 1H, J=8.46 Hz),8.01 (d, 1H, J=16.37 Hz), 7.91 (s, 1H), 7.83 (td, 1H, J=7.69 Hz, J=1.77Hz), 7.78 (d, 1H, J=1.73), 7.70 (d, 1H, J=7.78 Hz), 7.59-7.70 (m, 3H),7.50 (d, 1H, J=8.01 Hz), 7.29 (qd, 1H, J=7.46 Hz, J=1.02 Hz), 6.86 (s,1H), 5.95 (m, 1H), 4.93-5.10 (m, 4H), 2.34 (s, 3H), 2.22 (s, 3H). LCMS(ESI+) [M+H]/z Calc'd 503, found 503. Anal. Calc'd: C, 71.70; H, 5.21;N, 16.72. Found: C, 70.98; H, 5.42; N, 15.94.

Example 41(gg):6-(3-acetamido-4-methylbenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0776]

[0777] Example 41(gg) was prepared in a similar manner to that describedfor Example 41(ee), except that acetyl chloride was used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (CD₃OD) δ 8.57(d, 1H, J=4.90 Hz), 8.13 (d, 1H, J=8.49 Hz), 7.99 (s, 1H), 7.95 (d, 1H,J=16.53 Hz), 7.89 (d, 1H, J=1.46 Hz), 7.86 (td, 1H, J=7.64 Hz, J=1.73Hz), 7.73 (d, 1H, J=7.05 Hz), 7.62-7.69 (m, 2H), 7.65 (d, 1H, J=16.48Hz), 7.44 (d, 1H, J=7.97 Hz), 7.32 (qd, 1H, J=7.44 Hz, J=1.03 Hz), 2.38(s, 3H), 2.18 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 397, found 397. Anal.Calc'd: C, 72.71; H, 5.08; N, 14.13. Found: C, 72.29; H, 5.09; N, 13.98.

Example 41(hh):6-[3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0778]

[0779] Example 41(hh) was prepared in a similar manner to that describedfor Example 41(ee), except that 2,5-dimethyl-2H-pyrazole-3-carboxylicacid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylicacid. HPLC R_(t): 3.92 min. (100% area). ¹H NMR (DMSO) δ 10.02 (s, 1H),8.74 (d, 1H, J=3.6 Hz), 8.49 (d, 1H, J=8.4 Hz), 8.13 (d, 1H, J=16.3 Hz),8.03 (s, 1H), 7.96-7.93 (m, 2H), 7.84-7.72 (m, 4H), 7.63 (d, 1H, 8.1Hz), 7.42 (dd, 1H, J=6.8, 1.5 Hz), 6.95 (s, 1H), 4.1 1 (s, 1H), 2.48 (s,1H), 2.32 (s, 1H).

Example 41(ii):6-[3-((1-n-propyl-3-methyl-1H-pyrazol-5-yl)carboxamido)4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0780]

[0781] Example 41(ii) was prepared in a similar manner to that describedfor Example 41 (ee), except that5-methyl-2-propyl-2H-pyrazole-3-carboxylic acid was used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R_(t) 4.16 min.(100% area). ¹H NMR (DMSO-d₆) δ 10.29 (s, 1H), 8.58 (d, 1H, 3.9 Hz),8.33 (d, 1H, J=8.4 Hz), 8.13 (s, 1H), 8.10 (dt, 1H, J=5.4, 2.1 Hz), 7.96(d, 1H, J=16.5 Hz), 7.87 (s, 1H), 7.78 (td, 1H, J=7.5, 1.5 Hz),7.61-7.49 (m, 6H), 7.24 (dd, 1H, J=6.9, 1.8 Hz), 4.32 (t, 2H, J=6.90Hz), 2.58 (s, 3H), 2.22 (s, 3H) 1.69 (q, 2H, J=7.2 Hz), 0.77 (t, 3H, 7.5Hz). HRMS (MALDI) C₃₀H₂6N₆O₂ [M+H⁺]/z: Calc. 505.2347, found 505.2343.

Example 41(jj):6-[3-((3-Ethyl-1-methyl-1H-pyrazol-5-yl)carboxamido)-4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0782]

[0783] Example 41(jj) was prepared in a similar manner to that describedfor Example 41(ee), except that5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid was used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 10.78(s, 1H), 9.43 (d, 1H, J=3.0 Hz), 9.15 (t, 1H, J=9.6 Hz), 8.82 (dd, 1H,J=16.4, 1.5 Hz), 8.72-8.61 (m, 2H), 8.52-8.30 (m, 4H), 8.10 (dd, 1H,J=6.9, 5.7), 7.93-7.89 (m, 1H), 7.72-7.69 (m, 1H), 4.85 (s, 3H), .39 (q,2H, J=7.8 Hz), 3.17 (s, 3H), 2.10 (t, 3H, J=7.5 Hz). HRMS (MALDI)C₂₉H₂₆N₆O₂ (M+H⁺) m/z: Calc. 491.2190, found 491.2211.

Example 41(kk):6-[3-((1-Isopropyl-3-methyl-1H-pyrazol-5-yl)carboxamido)4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0784]

[0785] Example 41(kk) was prepared in a similar manner to that describedfor Example 41 (ee), except that2-isopropyl-5-methyl-2H-pyrazole-3-carboxylic acid was used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R_(t) 4.11 min.(100% area). ¹H NMR (DMSO-d₆) δ 9.99 (s, 1H), 8.68 (d, 1H, J=3.6 Hz),8.42 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=16.4 Hz), 7.98 (s, 1H), 7.67-7.86(m, 2H), 7.77-7.65 (m, 4H), 7.56 (d, 1H, J=7.8 Hz), 7.37-7.33 (m, 1H),6.82 (s, 1H), 5.44-5.36 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 1.42 (d,6H, J=6.6 Hz). Anal. (C₃₀H₂₈N₆O₂0.2H₂O) Calc'd: C, 5.63; N, 16.54.Found C, 70.57; H, 5.70; N, 16.35.

Example 41(ll):6-[2,4-dimethyl-5-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0786]

[0787] Example 41(ll) was prepared in similar manner as Example 41(a)except that Example 40(c) was used in place of Example 40(a). ¹H NMR(DMSO-d₆) δ 13.6 (s, 1H), 9.82 (s, 1H), 8.63 (d, 1H, J=3.84 Hz), 8.35(d, 1H, J=8.54 Hz), 8.00 (d, 1H, J=16.37 Hz), 7.83 (s, 1H), 7.83 (td,1H, J=7.65 Hz, J=1.82 Hz), 7.69 (d, 1H, J=7.89 Hz), 7.65 (dd, 1H, J=8.52Hz, J=1.36 Hz), 7.62 (d, 1H, J=16.34 Hz), 7.35 (s, 1H), 7.32 (s, 1H),7.29 (qd, 1H, J=7.42 Hz, J=1.09 Hz), 6.78 (s, 1H), 4.39 (q, 2H, J=7.15Hz), 2.30 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 1.27 (t, 3H, J=7.15 Hz).LCMS (ESI+) [M+H]/z Calc'd 505, found 505.

Example 41(mm):6-[2,4-dimethyl-5-((1,3-dimethyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0788]

[0789] Example 41(mm) was prepared in a similar manner to that describedfor Example 41(11), except that 2,5-dimethyl-2H-pyrazole-3-carboxylicacid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylicacid. ¹H NMR (DMSO-d₆) δ 13.6 (s, 1H), 9.81 (s, 1H), 8.62 (d, 1H, J=3.81Hz), 8.35 (d, 1H, =8.6 Hz), 8.00 (d, 1H, J=16.36 Hz), 7.83 (dt, 1H,J=7.65 Hz, J=1.8 Hz), 7.8 (s, 1H), 7.69 (d, 1H, J=7.88 Hz), 7.65 (dd,1H, J=8.53 Hz, J=1.36 Hz), 7.62 (d, 1H, J=16.35 Hz), 7.36 (s, 1H), 7.32(s, 1H), 7.29 (qd, 1H, J=7.41 Hz, J=1.03 Hz), 6.79 (s, 1H), 3.96 (s,3H), 2.30 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H). LCMS (ESI+) [M+H]/zCalc'd 491, found 491. Anal. Calc'd: C, 71.00; H, 5.34; N, 17.13. Found:C, 70.69; H, 5.57; N, 16.26.

Example 41(nn) :6-(5-acetanido-2,4-dimethylbenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0790]

[0791] Example 41(nn) was prepared in a similar manner to that describedfor Example 41(11), except that acetyl chloride was used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 13.6(bs, 1H), 9.34 (s, 1H), 8.62 (d, 1H, J=4.15 Hz), 8.33 (d, 1H, J=8.6 Hz),7.86 (d, 1H, J=16.36 Hz), 7.83 (td, 1H, J=7.71 Hz, J=1.82 Hz), 7.81 (s,1H), 7.69 (d, 1H, J=7.84 Hz), 7.64 (dd, 1H, J=1.38 Hz), 7.62 (d, 1H,J=16.46 Hz), 7.48 (s, H), 7.29 (qd, 1H, J=7.44 Hz, J=1.02 Hz), 7.24 (s,1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.02 (s, 3H). LCMS (ESI+) [M+H]/zCalc'd 411, found 411.

[0792] Examples 41(oo)-41(lll) can be prepared in a similar manner tothat described for Example 41 (a).

Example 41(oo)

[0793]

Example 41(pp)

[0794]

Example 41(qq)

[0795]

Example 41(rr)

[0796]

Example 41(ss)

[0797]

Example 41(tt)

[0798]

Example 41(uu)

[0799]

Example 41(vv)

[0800]

Example 41(ww)

[0801]

Example 41(xx)

[0802]

Example 41(yy)

[0803]

Example 41(zz)

[0804]

Example 41(aaa)

[0805]

Example 41(bbb)

[0806]

Example 41(ccc)

[0807]

Example 41(ddd)

[0808]

Example 41(eee)

[0809]

Example 41(ff)

[0810]

Example 41(ggg)

[0811]

Example 41(hhh)

[0812]

Example 41(iii)

[0813]

Example 41(jjj)

[0814]

Example 41(kkk)

[0815]

Example 41(lll)

[0816]

Example 42(a):6(3-Benzamidobenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0817]

[0818] Example 42(a) was prepared from6-(3-benzamidobenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazolein a similar manner as that of Example 12. (0.58 g, 80.6%). HPLC 4.13min (98% area). ¹H NMR (CDCl₃) δ 8.66 (d, 1H, J=4.1 Hz), 8.24 (d, 1H,J=8.5 Hz), 8.11-8.10 (m, 3H), 8.01-7.98 (m, 4H), 7.83 (t, 2H, J=7.1 Hz),7.72-7.53 (m, 7H), 7.30 (qd, 1H, J=5.2, 1.1 Hz). HRMS (MALDI)C₂₆H₂ON₄O₂[M+H⁺]/z: Calc. 445.1664, found 445.1659. Anal.(C₂₆H₁₉N₅O₂0.2EtOAc): C, 75.87; H, 4.78; N, 12.39.

[0819] The starting material was prepared as follows:

[0820] To a stirred solution of6-iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(4.00 g, 8.40 mmol), from Example 14 step (i), in anisole (48 mL) underan argon atmosphere were added bis(triphenylphosphine)palladiumdichloride (176 mg, 0.25 mmol), TBACI (288 mg, 1.0 mmol), 2-butanol(1.54 mL, 16.8 mmol) and potassium carbonate (3.48 g, 25.2 mmol). Theresulting mixture was stirred under a carbon monoxide atmosphere at 80°C. for 100 h. After removal of the solvent by in vacuo concentration,the residue obtained was diluted with EtOAc (400 mL) and extracted withsat. NaCi (2×150 mL), sat. NaHCO₃ (2×50 mL) and water (2×50 mL) thenorganic layer filter through 20 mL of silica. The organic filtrate wasthen concentrated in vacuo, to give an amber oil. Purification by flashchromatography with hexane:EtOAc (7:3) provided6-(3-aminobenzoyl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas an amber oil upon concentration (2.38 g, 61% yield). ¹H NMR (CDCl₃) δ8.84 (dd, 1H, J=8.70,0.90 Hz), 8.02 (s, 1H), 7.77 (dd, 1H, J=8.40, 1.50Hz), 7.62-7.59 (m, 2H), 7.40 (t, 2H, J=7.20 Hz), 7.38-7.24 (m, 4H),7.22-7.19 (m, 3H), 6.98 (dq, 1H, J=8.30, 0.90 Hz), 3.83 (brs, 2H,), 3.61(t, 2H, J=8.10 Hz), 0.91 (t, 2H, J=7.20 Hz), −0.17 (s, 9H).

[0821] To a stirred solution of6-(3-aminobenzoyl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(3.22 g, 6.87 mmol) in methylene chloride (10 mL) under an argonatmosphere was added benzoyl chloride (0.95 mL, 8.37 mmol) and pyridine(0.67 mL, 3.22 mmol). After 2 h the solution was diluted with 100 mL ofEtOAc and washed with saturated NaCI (1×50 mL), citric acid (IM, 2.5 pH,2×50 mL) and (50:50) NaHCO_(3/)water (2×50 mL). The organic layer wasdried over Na₂SO₄ and filtered through 20 mL of silica. The organiclayer was concentrated in vacuo, to provide the product as a yellowsolid. Purification using flash chromatography through silica elutingwith hexane:EtOAc (7:3) afforded6-(3-benzamidobenzoyl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas a yellow foam (3.22 g, 85.1% yield). ¹H NMR (CDCl₃) δ 8.19 (d, 1H,J=8.7 Hz), 8.16 (s, 1H,), 8.11-8.10 (m, 2H), 8.03-7.93 (m, 3H), 7.82(dd,1H, J=8.4, 1.2 Hz), 7.70-7.67 (m, 3H), 7.64-7.54 (m, 5H), 7.48 (t, 2H,J=14.1 Hz) 7.39 (1H, d, J=7.2 Hz).

[0822] A stirred solution of6-(3-benzamidobenzoyl)-3-((E)-styryl)-1-(²-trimethylsilanyl-ethoxy-methyl)-1H-indazole(2.35 g, 4.07 mmol) in methylene chloride (45.6 mL) was cooled to -45°C. using acetonitrile/solid carbon dioxide bath. Ozone was then bubbledthrough the solution at a rate of 1.5 Lpm, 60 amps for 15 minutes. Thereaction mixture was quenched with the addition of hydrogen sulfide (2.5mL) and warmed to 25° C. Removal of methylene chloride was accomplishedby in vacuo concentration. The residue was purified through silicaeluting with hexane:EtOAc (7:3) afforded6-(3-benzamidobenzoyl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-indazole-3-carboxaldehydeas an off-white foam (1.74 g, 85% yield). HPLC. 3.78 min (100% area); ¹HNMR (DMSO-d₆) δ 10.77 (s, 1H), 10.42 (s, 1H), 8.46-8.39 (m, 2H), 8.31(dt, 1H, J=6.0, 1.8 Hz), 8.19 (s, 1H,), 8.11-8.07 (m, 2H,), 7.91 (dd,1H, J=6.0, 1.2 Hz), 7.70-7.64 (m, 5H), 5.81 (s, 2H) 3.68 (t, 2H, J=6.9Hz), 0.98 (t, 2H, J=6.7 Hz), 0.02 (s, 9H).

[0823] To a stirred solution of 2-picolytriphenyphosphonium chloridew/sodium hydride (2.23 g, 4.91 mmol) cooled to −78° C. was added6-(3-benzamidobenzoyl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-indazole-3-carboxaldehyde(1.26 g, 2.46 mmol) in 5 mL of THF anhydrous under an argon purge andstirred for lh at 0° C. and quenched via CH₃COOH/MeOH (1:1, lmL). Thereaction mixture was diluted with 100 mL of EtOAc and partitionedbetween saturated NaCI (1×50 mL), and saturated NaHCO₃ (2 x 50 mL) thenthe organic layer dried over Na₂SO₄ and filter through 20 mL of silicaplug (3:1 trans/cis mixture). Purification with a 4 mm silica rotoreluting with hexane/EtOAc (1:1) afford6-(3-benzamidobenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleafter concentration as a yellow solid (1.05 g, 62%). ¹H NMR (CDCl₃) δ8.62 (d, 1H, J=4.1 Hz), 8.22 (d, 1H, J=8.5 Hz), 8.11-8.10 (m, 3H),8.01-7.98 (m, 4H), 7.83 (t, 2H, J=7.1 Hz), 7.72-7.53 (m, 7H), 7.30 (qd,1H, J=5.2, 1.1 Hz), 5.81 (s, 2H) 3.68 (t, 2H, J=6.9 Hz), 0.98 (t, 2H,J=6.7 Hz), 0.02 (s, 9H).

Example 42(b):6-(3-Benzanidobenzoyl)-3-(1H-benzoimidazol-2-yl)-1H-indazole

[0824]

[0825] Example 42(b) was prepared in a similar manner to that describedfor Example 42(a) except that step (iv) was replaced by the following:To the aldehyde prepared in Example 42(a), step (iii) was added1,2-diaminobenzene (0.011 g, 011 mmol), elemental sulfur (USP grade, 0.4g, 0.1201 mmol), 2 mL of anhydrous DMF and the mix was warmed to 90° C.for 18h, cooled to 25° C. The reaction mixture was diluted with 10 mL ofethyl acetate and was washed with saturated NaCi (1×10 mL), NaHCO₃ (1×10Ml) and water 10 mL, dried over NaSO₄ and filter though a teflon filter0.22 μM and concentrated to a amber oil. Purification by radialchromatography followed by precipitation from 2 mL of methylene chlorideand hexane (2 mL) afforded intermediate as a white precipitated. ¹H NMR(Acetone-d6) δ 8.81 (d, 1H, J=8.6), 8.30-8.25 (m, 2H), 8.11 (s, 1H),8.02-7.99(m, 2H), 7.79 (td, 2H, J=12.2, 1.2 Hz), 7.63-7.47 (m, 7H),7.28-7.40 (m, 2H). HRMS (MALDI) m/Z C₂₈H₁₉N₅O₂ Calc. (M+H+): 458.1617,found 458.1632.

Example 42(c):6-(3-Benzamidobenzoyl)-3-E-[2-(2-methylthiazol-4-yl)ethenyl]-1H-indazole

[0826]

[0827] Example 42(c) was prepared in similar manner as 42(a) except4-(2-methylthiazyl)-methyltriphenylphosphonium chloride was used inplace of 2-picolytriphenyphosphonium chloride in step (iv). ¹H NMR(DMSO) δ 8.11-8.01 (m, 4H), 7.92 (d, 2H, J=6.9 Hz), 7.76-7.71 (m, 2H),7.65-7.62 (m, 1H), 7.56-7.48 (m, 5H,), 7.15 (s, 1H,). 2.81 (s, 3H). HRMS(MALDI) C₂₇H₂₀N₄O₂S M+H⁺/z: Calc. (M+H+) 465.1380, found 465.1373.

Example 42(d):6-(3-benzamidobenzoyl)-3-(3H-imidazo[4,5-b]pyridin-2-yl)-1H-indazole

[0828]

[0829] Example 42(d) was prepared in similar manner as 42(b) except1,2-diamine-2-pyridine was used in place of 1,2-diaminebenzene. HPLC:3.88 min (95% area); ¹H NMR (DMSO-d₆) δ 10.62 (s, 1H), 8.83 (d, 1H,J=8.4 Hz), 8.53 (s, 1H), 8.43 (s, 1H), 8.32 (dt, 1H, J=6.9, 1.8 Hz),8.15 (d, lh, J=12.9 Hz), 8.11-8.10 (m, 2H), 7.91 (d, 1H, J=9.0 Hz),7.72-7.65 (m, 6H), 7.43 (dd, 1H, J=6.3, 4.8 Hz). HRMS (MALDI) m/zC₂₇H₁₈N₆O₂ Calc. (M+H⁺): 459.1564, found 459.1558. Anal.(C₂₇H₁₈N₆O₂0.4CH₂Cl₂): Calc. C, 66.83; H, 3.85; N, 17.07. Found: C,66.93; H, 4.04, N, 16.68.

Example 42(e):6-(3-benzamidobenzoyl)-3-E-[N-(4H-1,2,4-triazol-4-yl)iminomethyl]-1H-indazole

[0830]

[0831] Example 42(e) was prepared in a similar manner as Example 42(a)except that 4-amino-1,2,4 triazole and PPTS were used at 80° C. in placeof 2-picolytriphenyphosphonium chloride and potassium hydride at 23° C.HPLC Rt: 4.05 min (96% area); ¹H NMR (DMSO-d₆) δ 10.58 (s, 1H), 9.53 (s,1H), 9.40 (s, 2H), 8.56 (d, 1H, J=8.4 Hz), 8.38 (s, 1H), 8.26 (dt, 1H,J=7.2, 2.1 Hz), 8.13 (s, 1H), 8.08-8.05 (m, 2H), 7.73-7.67 (m, 5H). HRMS(MALDI) C₂₄H₁₇N₇O₂ [M+H⁺]/z: Calc. 436.1516, found 436.1510. Anal.(C₂₄H₁₇N₇O₂0.4hexane) Calc. C, 66.18; H, 4.67; N, 20.47. Found: C,65.78; H, 4.87, N, 20.47.

Example 43:6-(3-Benzaniidobenzoyl)-3-E-[2-(2-formamidophenyl)ethenyl]-1H-indazole

[0832]

[0833] Example 43 was prepared from6-(3-benzamidobenzoyl)-3-E-(2-formamidophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazolein a similar manner to that described for Example 11. 18 mg (36%). HPLCR_(t): 4.19 min. ¹H NMR (CDCl₃) δ 8.43-7.92 (m, 6H), 7.68-7.49 (m, 4H)7.39-7.36 (m, 3H), 7.32-7.21 (m, 2H), 7.09-7.00 (m, 2H), 6.91-6.84 (m,1H). HRMS (MALDI) C₃₀H₂₂N₄O₃ [M +Na]/z: Calc.509.1590, found 509.1580.Anal. (C₃₀H₂₂N₄O₃0.3H O) Calc'd: C, 73.25; H, 4.63; N, 11.39. Found: C,73.10; H, 4.58; N, 11.28.

[0834] Starting material was prepared as follows:

[0835] 6-(3-Benzamidobenzoyl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-indazole-3-carboxaldehyde (prepared in Example 42(a), step (iii)) wasconverted to6-(3-benzamidobenzoyl)-3-E-(2-nitrophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazole in similar manner to that of Example 42(a), step (iv) exceptthat (2-nitrobenzyl)triphenylphosphonium bromide monohydrate was used inplace 2-picolytriphenyphosphonium chloride (0.19 g, 79%). ¹H NMR (CDCl₃)δ 8.15-7.93 (m, 5H), 7.89-7.86 (m, 3H), 7.54-7.41 (m, 6H), 7.36-7.35 (m,2H), 7.21-7.18 (m, 2H), 7.03-6.91 (m, 1H), 3.64-3.46 (m, 2H), 0.96-0.79(m, 2H), -0.06 (s, 9H).

[0836]6-(3-Benzamidobenzoyl)-3-E-(2-nitrophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(0.19,0.32 mmol) was dissolved in 3 mL of DMF, treated with SnCl₂ (0.26g, 1.40 mmol) and water (0.037 mL, 1.87 mmol), and was stirred for 3h at50° C. The reaction was quenched at 25° C. with 0.5 mL of 3N NaOH andthe precipitate was removed by filtration through celite. The solutionwas then partitioned between 50/50 saturated NaHCO_(3/)water (2×30 mL)and the organic layer was filtered through a silica plug to give6-(3-benzamidobenzoyl)-3-E-(2-aminophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas an amber oil (0.17 g, 92%).

[0837] Product was used without further purification.

[0838]6-(3-Benzamidobenzoyl)-3-E-(2-aminophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(0.17, 0.28 mmol) was dissolved in 3 mL of methylene chloride. To thiswas added formic acid pentafluorophenyl ester (0.12 g, 0.56 mmol)dropwise. After 3h, the reaction mixture was diluted with 40 mL of EtOAcand was washed with 50/50 NaHCO₃ (2×30 mL) and the organic layer wasfiltered through a silica plug. The residue was purified by radialchromatography through silica eluting with hexane:EtOAc/CH₂CI2 (1:1:1)which afforded6-(3-benzamidobenzoyl)-3-E-(2-formamidophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas a clear oil (63 mg, 40%). ¹H NMR (CDCl₃) δ 8.48-8.36 (m, 1H),8.20-7.84 (m, 4H), 7.61-7.52 (m, 5H), 7.41-7.32 (m, 4H), 7.26-7.01 (m,4H), 6.82 (t, 1H, J=14.2 Hz), 3.48-3.23 (m, 2H), 0.95-0.87 (m, 2H),-0.05 (s, 9H).

Example 44:6(3-Aminobenzoyl)-3-E-[N-(pyrrol-1-yl)iminomethyl]-1H-indazole

[0839]

[0840] Example 44 was prepared from the starting material describedbelow in a similar manner to that described for Example 12. R_(f) sm0.6, p 0.5 (ethyl acetate): ¹H NMR (300 MHz, CDCl₃) δ 8.8 (s, 1H), 8.5(d, 1H), 7.95 (s, 1H), 7.75 (d, 1H), 7.45-7.3 (m, 7H), 7.2 (m, 1H), 6.40(s, 2H).

[0841] The starting material was prepared as follows:

[0842] Aldehyde prepared in Example 33(a), step (i) (204 mg, 0.507 mmol)and 1-aminopyrrole (67 μL, 0.66 mmol, 1.3 equiv) were stirred togetherin toluene (2 mL). To this mix was added PPTS (1 mg) and the solutionwas heated to 80° C. for 1 h. The mixture was cooled and was partitionedbetween 2:8 ethyl acetate-hexane and water. The organic material wasdried over sodium sulfate, decanted and concentrated under reducedpressure. The product was crystallized from dichloromethane (0.5 mL) andmethanol (2 mL) (215.7 mg, 91%): ¹H NMR (300 MHz, C6D₆) δ 8.71 (s, 1H),8.25 (d, 1H, J=8.5 Hz), 8.08 (s, 1H), 7.75 (d, 1H, J=8.5 Hz), 6.35 (s,2H), 5.85 (s, 2H).

[0843] A mixture of the above iodide (535 mg, 1.15 mmol, 1 equiv),3-aminophenyl boronic acid (236 mg, 1.72 mmol, 1.5 equiv), PdCl₂(PPh₃)₂(24 mg, 0.034 mg, 0.03 equiv), and potassium carbonate were taken up inanisole (6.7 mL) under carbon monoxide (1 atm). The mixture was heatedto 80° C. for 14 h. The mix was cooled, partitioned between ethylacetate and water. The organics were washed with saturated aqueoussodium bicarbonate, water and brine and the organic layer was separated.The organic material was dried over sodium sulfate, decanted andconcentrated under reduced pressure. Purification by silica gelchromatography (50 mL silica: 2:8 to 3:7 ethyl acetate-hexane) gaveproduct aniline as a solid (331 mg, 63%): R_(f) sm 0.60, p 0.21 (ethylacetate-hexane 3:7); ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 8.51 (d,1H, J=8.4 Hz), 8.06 (s, 1H), 7.76 (dd, 1H, J=1.3, 8.4 Hz), 7.26 (m, 3H),7.17 (m, 2H), 6.92 (m, 1H), 6.31 (t, 1H, J=2.3 Hz), 5.79 (s, 2H), 3.84(bs, 2H), 3.60 (t, 2H, J=8.2 Hz), 0.91 (t, 2H, J=8.2 Hz), -.08 (s, 9H).LCMS 4.98 min (pos) [M+H]/z Calc'd 460, found 460.

Example 45(a):6-[3-(Indol-4-ylcarboxamido)benzoyl]-3-E-[N-(pyrrol-1-yl)iminomethyl]-1H-indazole

[0844]

[0845] Example 45(a) was prepared from Example 44 in a similar manner tothat described for Example 12(d), except that indole4-carboxylic acidwas used instead of 5-methyl-thiazole-2-carboxylic acid: R_(f) sm 0.0, p0.2 (ethyl acetate-benzene 1:3); ¹H NMR (300 MHz, dmso-d6) 8 9.84 (s,1H), 8.92 (s, 1H), 8.66 (s, 1H), 8.39 (d, 1H, J=8.5 Hz), 8.02 (s, 1H),7.86 (m, 2H), 7.66 (d, 1H, J=8.5 Hz), 7.52-7.40 (m, 4H), 7.27-7.07 (m,5H), 6.83 (s, 1H), 6.21 (s, 2H).

Example 45(b):6-(3-Benzamidobenzoyl)-3-E-[N-(pyrrol-1-yl)iminomethyl]-1H-indazole

[0846]

[0847] Example 45(b) was prepared from Example 44 in a similar manner tothat described for Example 12(d), except that benzoyl chloride was usedinstead of 5-methyl-thiazole-2-carboxylic acid and HATU: ¹H NMR (300MHz, CDCl₃) δ 11.9 (bs, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.39 (d, 1H,J=8.4 Hz), 7.99 (s, 1H), 7.9-7.8 (m, 4H), 7.65 (d, 1H, J=8.4 Hz), 7.48(t, 2H, J=7.8 Hz), 7.42-7.35 (m, 3H), 7.20 (t, 2H, 2.2 Hz), 6.28 (t, 2H,J=2.2 Hz).

Example 46: 6-[N-(3-aminophenyl)am no]-3-E-styyl-1H-indazole

[0848]

[0849] Example 46 was prepared from the starting material describedbelow in a similar manner to that described for Example 13(i). ¹H NMR(300 MHz, DMSO-d₆) δ 12.6 (s, 1H), 8.07 (s, 1H), 7.97 (d, 1H, J=8.73Hz), 7.69 (d, 1H, J=8.49 Hz), 7.40 (m, 4H), 7.28 (m, 1H), 7.06 (d, 1H,J=1.49 Hz), 6.44 (t, 1H, J=1.98 Hz), 6.34 (m, 1H), 6.14 (dd, 1H, J=7.88Hz, J=1.26 Hz), 5.01 (bs, 2H).

[0850] The compound prepared in Example 11, step (v), was converted to6-[N-(3-nitrophenyl)amino]-3-E-styryl-1H-indazole in a similar manner tothat described for Example 12. ¹H NMR (300 MHz, CDCl₃) δ 8.0 (m, 2H),7.77 (m, 1H), 7.64 (d, 2H, J=7.86 Hz), 7.41-7.56 (m, 6H), 7.33 (m, 2H),7.08 (d, 1H, J=8.67 Hz). MS (ESI+) [M+H]/z Calc'd 357, found 357.Calc'd: C, 70.77; H, 4.53; N, 15.72. Found: C, 69.18; H, 4.51; N, 15.30.

Example 47:6-[N-(3-benzanido-4-fluorophenyl)amino]-3-E-styryl1H-indazole

[0851]

[0852]6-[N-(3-Benzamido-4-fluorophenyl)amino]-1-(2-trimethylsilanyl-ethoxymethyl-3-E-styryl1H-indazolewas converted to Example 47 in a similar manner to that described forExample 11. ¹H NMR (300 MHz, DMSO-d₆) δ 12.6 (s, 1H), 10.0 (s, 1H)),8.38 (bs, 1H), 8.02 (d, 1H, J=8.78), 7.98 (d, 2H, J=6.87 Hz), 7.69 (d,2H, J=7.27 Hz), 7.48-7.61 (m, 4H), 7.45 (s, 2H), 7.40 (t, 2H, J=7.28Hz), 7.53-7.30 (t, 2H, J=7.28 Hz), 7.53-7.30 m, 2H), &0.07 (d, 1H,J=1.55 Hz), 7.03 (m, 1H), 6.95 (dd, 1H, J=8.79 Hz, J=1.85 Hz). MS (ESI+)[M+H]/z Calc'd 449, found 449. Anal. Calc'd: C, 74.98. H, 4.72. N,12.49. Found: C, 74.29. H, 4.76. N, 12.12.

[0853] The starting material was prepared as follows:

[0854] To a solution of 2-fluoro-5-nitro-phenylamine (3.12 g, 20 mmol)in dichloromethane (20 ml) at 23° C. under argon was added pyridine(1.94 ml, 24 mmol) and benzoyl chloride (2.8 ml, 24 mmol). After 45minutes a white precipitate formed. The reaction mixture wasconcentrated in-vacuo then diluted with water and filtered to give awhite solid which was re-suspended in MeOH and filtered again givingN-(2-fluoro-5-nitro-phenyl)-benzamide (4.86 g, 93%). H NMR (300 MHz,CDCl₃) δ 9.48 (dd, 1H, J=6.8 Hz, J=2.81 Hz), 8.17 (bs, 1H), 8.03 (m,1H), 7.92 (m, 2H), 7.52-7.65 (m, 3H), 7.31 (d, 1H, J=9.2 Hz).

[0855] A mixture of N-(2-fluoro-5-nitro-phenyl)-benzamide (4.86 g, 18.7mmol) and 10% Pd/C (486 mg) in a 1:1 mixture of THF-MeOH (80 ml) washydrogenated at 23° C. After 2.5 h the reaction mixture was filteredthrough celite and concentrated to giveN-(5-Amino-2-fluoro-phenyl)-benzamide (3.92 g, 91%). MS (ESI+) [M+H]/zCalc'd 231, found 231.

[0856]6-[N-(3-Benzamido-4-fluorophenyl)amino]-1-(2-trimethylsilanyl-ethoxymethyl-3-E-styryl1H-indazolewas prepared in a similar manner as Example 48(a), step (iii) exceptthat N-(5-amino-2-fluoro-phenyl)-benzamide, and the compound prepared inExample 14, step (i) were used as starting materials. ¹H NMR (300 MHz,CDCl₃) δ 8.38 (dd, 1H, J=6.84 Hz, J=2.73 Hz), 8.09 (d, 1H, J=3.08 Hz),7.86-7.91 (m, 3H), 7.48-7.61 (m, 5H), 7.28-7.45 (m, 4H), 7.19 (d, 1H,J=1.7 Hz), 7.08 (dd, 1H, J=10.48 Hz), 5 6.90-6.96 (m, 2H), 6.03 (bs,1H), 5.66 (s, 2H), 3.62 (t, 2H, J=8.14 Hz), 0.91 (t, 2H, J=8.32 Hz), 0.0(s, 9H). MS (ESI+) [M+H]/z Calc'd 579, found 579. Anal. Calc'd: C,70.56. H, 6.10. N, 9.68. Found: C, 20.26. H, 6.08. N, 9.16.

Example 48(a):6-[N-(5-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)-2-fluoro-4-methylphenyl)amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0857]

[0858] Example 48(a) was prepared in a similar manner as Example 41(a)from the starting material described below. ¹H NMR (300 MHz, CD₃OD) δ8.54 (d, 1H, J=4.8 Hz), 7.95 (d, 1H, J=9.49 Hz), 7.84 (td, 1H, J=7.71Hz, J=1.78 Hz), 7.70 (d, 1H, J=7.95 Hz), 7.53 (d, 1H, J=16.59 Hz), 7.40(d, 1H, J=7.92 Hz), 7.29 (qd, 1H, J=7.45 Hz, J=1.07 Hz), 7.11 (d, 1H,J=11.8), 7.03-7.06 (m, 2H), 6.71 (s, 1H), 4.50 (q, 2H, J=7.16 Hz), 2.27(s, 3H), 2.26 (s, 3H), 1.38 (t, 3H, J=7.11 Hz). MS (ESI+) [M+H]/z Calc'd496, found 496. Anal. Calc'd: C, 67.86; H, 5.29; N, 19.79. Found: C,66.24; H, 5.50; N, 18.61.

[0859] The starting material was prepared as follows:

[0860] A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (1.0 g, 5mmol) and 10% Pd/C (200 mg) in MeOH (20 ml) was hydrogenated at 23° C.for 24 h. The reaction mixture was filtered through celite andconcentrated. Purification by silica gel chromatography (1:1 ethylacetate-hexane) gave 4-fluoro-6-methyl-benzene-1,3-diamine (613 mg,87%).

[0861] To a solution of carbonic acid 4-nitro-phenyl ester2-trimethylsilanyl-ethyl ester (566 mg, 2 mmol) in DMF (4 ml) at 23° C.under an atmosphere of argon was added DMAP (12 mg, 0.1 mmol), DIEA(0.35 ml, 2 mmol) and 4-fluoro-6-methyl-benzene-1,3-diamine. Theresulting solution was heated to 50° C. for 48 h. The reaction mixturewas quenched with saturated NaHCO₃ (aq), extracted with EtOAc (3×20 ml).The EtOAc was removed in-vacuo, and the residue was re-dissolved in Et₂Othen washed with 3 N NaOH (aq), water, brine, dried with Na₂SO₄,filtered and concentrated. Purification by silica gel chromatography(2:8-7:3 ethyl acetate-hexane) gave(5-amino-4-fluoro-2-methyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (160 mg, 28%). MS (ESI+) [M+H]/z Calc'd634, found 634.

[0862] To a mixture of6-Iodo-3-((E)-2-pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(224 mg, 0.47 mmol), 5-amino4-fluoro-2-methyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (160 mg, 0.56 mmol), Cs₂CO₃ (214 mg, 0.66mmol), PdCl₂(PPh₃)₂ (5.4 mg, 0.0059 mmol) and BINAP (10 mg, 0.0176 mmol)under argon at 23° C. was added toluene (0.5 ml). The resulting mixturewas heated to 80° C. for 16 h. The reaction mixture was cooled to 23° C.then diluted with water (20 ml) and extracted with EtOAc (3×50 ml). Theorganics were washed with water (30 ml), brine (30 ml), dried withNa₂SO₄ filtered and the concentrated to a foam. Silica gel column (3:7ethyl acetate-hexane) provided{4-Fluoro-2-methyl-5-[3-((E)-2-pyridin-2-yl-vinyl)-1-(²-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-phenyl}-carbamicacid 2-trimethylsilanyl-ethyl ester (98 mg, 33%). TLC (7-3 hexane-ethylacetate) Rfsm 0.42, Rfp 0.23. ¹H NMR (CDCl₃) δ 8.64 (dd, 1H, J=4.79 Hz,J=0.86 Hz), 7.94 (d, 1H, J=8.71 Hz), 7.91 (bs, 1H), 7.86 (d, 1H, J=16.41Hz), 7.69 (td, 1H, J=7.72 Hz, J=1.8 Hz), 7.55 (d, 1H, J=16.44 Hz), 7.49(d, 1H, J=7.91 Hz), 7.17 (qd, 1H, J=7.44 Hz, J=0.98 Hz), 6.99 (dd, 1H,J=8.67 Hz, J=1.89 Hz), 6.93 (d, 1H, J=11.2 Hz), 6.25 (bs, 1H), 5.95 (d,1H, J=1.97 Hz), 5.70 (s, 2H), 4.25 (t, 2H, J=8.53 Hz), 3.60 (t, 2H,J=8.24 Hz), 2.22 (s, 3H) 1.04 (t, 2H, J=8.54 Hz), 0.9 (t, 2H, J=8.25Hz), 0.05 (s, 9H), 0.0 (s, 9H). 13C NMR (CDCl₃, 75 MHz) δ 156.0, 154.4,149.8, 142.9, 142.8, 142.5, 136.6, 132.1, 130.1, 130.5, 128.7, 128.5,124.3, 122.2, 122.0, 121.8, 118.2, 117.3, 117.0, 115.1, 95.2, 77.6,77.4, 66.5, 63.7, 17.9, 17.2, −1.3. FTIR cm⁻¹: 3326, 2947, 1716, 1617,1534,1514, 1244, 1057. MS (ESI+) [M+H]/z Calc'd 634, found 634.

[0863] The above aniline was prepared in a similar manner as Example 11.¹H NMR (300 MHz, CD₃OD) δ 8.54 (m, 1H), 7.91 (dd, 1H, J=8.74 Hz, J=0.58Hz), 7.83 (td, 1H, J=7.72 Hz, J=1.79 Hz), 7.80 (d, 1H, J=16.52 Hz), 7.69(d, 1H, J=7.98 Hz), 7.52 (d, 1H, J=16.58 Hz), 7.29 (qd, 1H, J=7.43 Hz,J=1.07 Hz), 6.94-6.99 (m, 2H), 6.83 (d, 1H, J=11.98 Hz), 6.82 (d, 1H,J=7.49 Hz), 2.15 (s, 3H). MS (ESI+) [M+H]/z Calc'd 360, found 360.

Example 48(b):6[N-(5-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)-2-fluoro-4-methylphenyl)amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0864]

[0865] Example 48(b) was prepared in a similar manner as Example 48(a)except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acid was used in placeof 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300 MHz,DMSO-d₆) 8 12.8 (s, 1H), 9.71 (s, 1H), 8.59 (m, 1H), 8.11 (s, 1H), 8.00(d, 1H, J=8.75 Hz), 7.87 (d, 1H, J=16.37 Hz), 7.80 (td, 1H, J=7.66 Hz,J=1.81 Hz), 7.64 (d, 1H, J=7.88 Hz), 7.49 (d, 1H, J=16.38 Hz), 7.34 (d,1H, J=8.16 Hz), 7.26 (m, 1H), 7.21 (d, 1H, J=12.14 Hz), 6.97 (dd, 1H,J=8.76 Hz), 6.88 (s, 1H), 6.79 (s, 1H), 3.98 (s, 3H), 2.20 (s, 3H), 2.19(s, 3H). MS (ESI+) [M+H]/z Calc'd 482, found 482. Anal. Calc'd: C,67.35; H, 5.02; N, 20.36. Found: C, 66.83; H, 5.25; N, 19.68.

Example 49(a):6-[N-(3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)-4-fluoro-phenyl)amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0866]

[0867] Example 49(a) was prepared in a similar manner as Example 48(a)except for the following: 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid wasused in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid; In step(iii), (5-Amino-2-fluoro-phenyl)-carbamic acid 2-trimethylsilanyl-ethylester, prepared as described below, was used instead of(5-amino-4-fluoro-2-methyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester, DME was the solvent andbiphenyl-2-yl-dicyclohexyl-phosphane was used as ligand. ¹H NMR (300MHz, CD₃OD) δ 12.7 (s, 1H), 9.94 (s, 1H), 8.48 (m, 1H), 8.40 (s, 1H),8.02 (d, 1H, J=6.77 Hz), 7.87 (d, 1H, J=16.37 Hz), 7.80 (d, 1H, J=7.63Hz, J=1.81 Hz), 7.64 (d, 1H, J=7.88 Hz), 7.49 (d, 1H, J=16.39 Hz), 7.42(dd, 1H, J=6.65 Hz, J=2.68 Hz), 7.24 (m, 2H), 7.06 (m, 2H), 6.96 (dd,1H, J=8.81 Hz, J=1.82 Hz), 6.85 (s, 1H), 4.0 (s, 3H), 2.20 (s, 3H). MS(ESI+) [M+H]/z Calc'd 468, found 468. Anal. Calc'd: C, 66.80; H, 4.74;N, 20.97. Found: C, 66.01; H, 4.72; N,

[0868] To a solution of 1-Fluoro-2-isocyanato-4-nitro-benzene (9.82 g,54 mmol) in THF (40 ml) at 23° C. under an atmosphere of argon was added2-Trimethylsilanyl-ethanol (7.72 ml, 54 mmol). The resulting mixture wasstirred for 11 hours then heated to 50° C. for 2 hours. The reactionmixture was allowed to cool to 23° C. quenched with saturated NaHCO₃(aq) and extracted with EtOAc (3×100 ml). The pooled ethyl acetate waswashed with IN HCl (aq) (2×90 ml) water (90 ml) and brine (90 ml), driedwith Na₂SO₄, filtered and concentrated to a yellow solid. Silica gelchromatography (2:8 ethyl acetate-hexane) provided(2-Fluoro-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester(12.3 g, 77%). ¹H NMR (300 MHz, CDCl₃) δ 9.06 (dd, 1H, J=6.89 Hz, J=2.63Hz), 7.89 (m, 1H), 7.20 (m, 1H), 6.91 (bs, 1H), 4.31 (t, 2H, J=8.67 Hz),1.06 (t, 2H, J=8.67 Hz), 0.05 (s, 9H). LCMS (ESI−) [M+H]/z Calc'd 299,found 299.

[0869] A mixture of (2-Fluoro-5-nitro-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (3.00 g, 10 mmol) and 10% Pd/C (300 mg)in methanol (30 ml) was hydrogenated at 23° C. The resulting mixture wasstirred for 24 h. The reaction mixture was filtered through celite andconcentrated to give (5-Amino-2-fluoro-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (2.62 g, 97%). ¹H NMR (300 MHz, CDCl₃) δ7.52 (m, 1H), 6.85 (dd, 1H, J=10.8 Hz, J=8.69 Hz), 6.73 (bs, 1H), 6.28(m, 1H), 4.27 (t, 2H, J=8.57 Hz), 3.0-4.4 (bs, 2H), 1.06 (t, 2H, J=8.58Hz), 0.07 (s, 9H).

Example 49(b):6-[N-(3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)4-methylphenyl)amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0870]

[0871] Example 49(b) was prepared in a similar manner to Example 49(a)except that 1-methyl-²-isocyanato-4-nitro-benzene was used instead of1-Fluoro-2-isocyanato-4-nitro-benzene in step (i). ¹H NMR (300 MHz,CDCl₃) δ 8.59 (m, 1H), 8.35 (s, 1H), 8.00 (d, 1H, J=8.73 Hz), 7.87 (d,1H, J=16.38 Hz), 7.80 (td, 1H, J=7.66 Hz, J=1.85 Hz), 7.64 (d, 1H,J=7.85 Hz), 7.49 (d, 1H, J=16.35 Hz), 7.26 (m, 1H), 7.19 (m, 2H), 7.09(d, 1H, J=1.48 Hz), 7.02 (dd, 1H, J=8.17 Hz, J=2.24 Hz), 6.97 (dd, 1H,J=8.79 Hz, J=1.80 Hz), 6.81 (bs, 1H), 4.00 (s, 3H), 2.20 (s, 3H), 2.18(s, 3H). LCMS (ESI+) [M+H]/z Calc'd 464, found 464.

Example 49(c):6-[N-(3-acetamido-4-fluorophenyl)amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0872]

[0873] Example 49(c) was prepared in a similar manner to Example 49(a)except that acetic anhydride was used instead of2,5-dimethyl-2H-pyrazole-3-carboxylic acid: ¹H NMR (300 MHz, CD₃OD) δ8.44 (m, 1H), 7.82 (d, 1H), 7.70 (m, 3H), 7.55 (d, 1H), 7.41 (d, 1H,J=16.4 Hz), 7.19 (m, 1H), 7.03 (s, 1H), 6.94 (m, 1H), 6.87 (m, 2H), 2.11(s, 3H). LCMS (100% area) Rt=4.53 min, (pos) [M+H]/z Calc'd 388.4, found388.4.

[0874] Examples 49(d)49(x) can be prepared in a similar manner to thatdescribed for Example 49(a).

Example 49(d)

[0875]

Example 49(e)

[0876]

Example 49(f)

[0877]

Example 49(g)

[0878]

Example 49(h)

[0879]

Example 49(i)

[0880]

Example 49(j)

[0881]

Example 49(k)

[0882]

Example 49(l)

[0883]

Example 49(m)

[0884]

Example 49(n)

[0885]

Example 49(o)

[0886]

Example 49(p)

[0887]

Example 49(q)

[0888]

Example 49(r)

[0889]

Example 49(s)

[0890]

Example 49(t)

[0891]

Example 49(u)

[0892]

Example 49(v)

[0893]

Example 49(w)

[0894]

Example 49(x)

[0895]

Example 50:6-[3-(5-amino-2-fluorophenyl)carbamoyl-5-methyl-2-ethyl-2H-pyrazol-4-yl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0896]

[0897] Example 50 was prepared from the starting material describedbelow in a similar manner to that described for Example 11. MS (ESI+)[M+H]/z Calc'd 482, found 482. Calc'd: C, 67.35; H, 5.02; N, 20.36.Found: C, 66.70; H, 5.09; N, 19.95.

[0898] 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid(2-fluoro-5-nitro-phenyl)-amide was prepared in a similar manner asExample 47, step (i) except that2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid and HATU were usedinstead of benzoyl chloride. MS (ESI+) [M+H]/z Calc'd 293, found 293.

[0899] 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid(2-fluoro-5-nitro-phenyl)-amide was prepared in a similar manner as40(b), step (i). MS (ESI+) [M+H]/z Calc'd 263, found 263.

[0900]6-[3-(5-amino-2-fluorophenyl)carbamoyl-5-methyl-2-ethyl-2H-pyrazol-4-yl]-3-E-[2-(pyridin-2-yl)ethenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazolewas prepared in a similar manner as Example 48(a), step (iii) except2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid(5-amino-2-fluoro-phenyl)-amide was used as starting material. MS (ESI+)[M+H]/z Calc'd 612, found 612.

Example 51: 6-pyrid-4-yl-3-E-(N-(pyrrol-1-yl)iminomethyl)-1H-indazole

[0901]

[0902]6-Pyrid-4-yl-3-E-(N-(pyrrol-1-yl)iminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazolewas converted to6-pyrid-4-yl-3-E-(N-(pyrrol-1-yl)iminomethyl)-1H-indazole in a similarmanner to that described for Example 29(a). ¹H NMR (300 MHz, CDCl₃) δ8.76 (s, 1H), 8.67 (d, 2H, J=6.1 Hz), 8.53 (d, 1H, J=8.4 Hz), 7.74 (s,1H), 7.61 (d, 2H, J=6.2 Hz), 7.54 (d, 1H, J=8.5 Hz), 7.27-7.25 (m, 2H),6.31-6.29 (m, 2H). MS (ES) [M+H]/z Calc'd 288, found 288. Anal. Calc'd,C (71.07), H (4.56), N (24.37). Found: C (70.81), H (4.57), N (24.14).

[0903] The starting material was prepared as follows:

[0904] A solution of6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde(208 mg, 0.59 mmol), N-aminopyrrole (145 mg, 1.76 mmol), and acetic acid(5.8 μl) in ethanol (1 ml) was held at 95° C. for 16 h. The solution wasthen evaporated under reduced pressure, and purified by silica gelchromatography to give6-pyridyl-3-E-(N-(pyrrol-1-yl)iminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas an oil (140 mg, 57%). ¹H NMR (300 MHz, CDCl₃) δ 9.08 (s, 1H), 8.71(d, 2H, J=6.1 Hz), 8.46 (d, 1H, J=8.5 Hz), 8.34 (s, 1H), 7.85 (d, 2H,J=6.2 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.56 (t, 2H, J=2.3 Hz ), 6.25 (t, 2H,J=2.3 Hz), 5.93 (s, 1H), 5.74 (s, 2H), 3.64 (t, 2H, J=7.9 Hz), 0.86 (t,2H, J=7.9 Hz), 0.00 (s, 9H).

Example 52(a): 6-(7-azaindazol4-yl)-3-E-styryl-1H-indazole

[0905]

[0906] Sem-Example 52(a) was converted to Example 52(a) in a similarmanner to that described for Example 27(a). ¹H NMR (300 MHz, DMSO-d₆) δ8.63 (d, 1H, J=4.8 Hz), 8.41 (d, 1H, J=8.5 Hz), 8.37 (s, 1H), 7.99 (s,1H), 7.76 (d, 2H, J=7.3 Hz), 7.70 (d, 1H, J=8.5 Hz), 7.60-7.85 (m, 6H).HRMS (FAB) [M+H]/z Calc'd 338.1400, found 338.1389. Analyzed with 1.1trifluoroacetic acid, Calc'd, C (60.21), H (3.51), N (15.13). Found: C(59.93), H (3.59), N (14.86).

[0907] The starting material was prepared as follows:

[0908] A solution of3-styryl-1-(2-trimethylsilanyl-ethoxymethyl)-6-trimethylstannyl-1H-indazole(1.0 g, 1.90 mmol), 1-(4iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (0.56g, 1.90 mmol), AsPh₃ (116 mg, 0.38 mmol), and Pd₂dba₃ (87 mg, 0.09 mmol)in degassed dioxane (10 ml) was heated at 110° C. for 3 h. The solutionwas then diluted with ethyl acetate (50 ml), washed with brine (2×10ml), dried over MgSO₄, and concentrated under reduced pressure.Purification by silica gel chromatography gave Example 52(a) as a whitesolid (412 mg, 46%). ¹H NMR (300 MHz, CDCl₃) δ 8.82 (d, 1H, J=5.8 Hz),8.52 (s,1H), 8.29 (d, 1H, J=8.2 Hz), 8.05 (s, 1H), 7.73-7.32 (m, 10H),5.86 (s, 2H), 3.69 (t, 2H, J=8.2 Hz), 0.97 (t, 2H, J=8.2 Hz), −0.03 (s,9H).

[0909] A solution of6-iodo-3-styryl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (2.90 g,6.10 mmol), hexamethylditin (2.00 g, 6.12 mmol), and Pd(PPh₃)₄ (282 mg,0.24 mmol) in degassed dioxane (10 ml) was heated at 110° C. for 3 h.The solution was then diluted with ethyl acetate (200 ml), washed withbrine (2×20 ml), dried over MgSO₄, and evaporated under reducedpressure. Purification by silica gel chromatography gave 3-styryl--(2-trimethylsilanyl-ethoxymethyl)-6-trimethylstannyl-1H-indazole as ayellow oil (3 g, 96%). ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, 1H, J=7.4 Hz),7.71 (s, 1H), 7.71-7.29 (m, 8H), 5.77 (s, 2H), 3.65 (t, 2H, J=16.3 Hz),0.95 (t, 2H, J=16.4 Hz), 0.38 (s, 9H), 0.03 (s, 9H).

[0910] A mixture of 4-chloro-1H-pyrazolo[3,4-b]pyridine (820 mg, 5.30mmol), sodium iodide (2.4 mg, 16.0 mmol), and acetyl chloride (0.8 ml)in acetonitrile (6 ml) was refluxed 8 h. The mixture was then treatedwith a 10% aqueous solution of NaCO₃ (10 ml), and a 10% aqueous solutionof NaHSO₃ (10 ml), and held 10 min. The mixture was extracted with ethylacetate (50 ml), and the organics were washed with brine (10 ml), driedover MgSO₄, and evaporated under reduced pressure. Purification bysilica gel chromatography gave1-(4-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone as a brown solid (650mg, 42%). ¹H NMR (300 MHz, CDCl₃) δ 8.39 (d, 1H, J=5.0 Hz), 8.04 (s,1H), 7.76 (d, 1H, J=5.0 Hz), 2.88 (s, 3H).

[0911] 1,7-Dihydro-pyrazolo[3,4-b]pyridin4-one (1.2 g, 8.8 mmol) (Dorn,H. et al., Prakt. Chem., 324, 557-62 (1982)) in POC1₃ (15 ml) at 0° C.was treated with PCl₅ (2.5 mg, 0.01 mmol). The solution was allowed towarm to rt over 1 h, then heated to 90° C. and held 3h. The solution wasconcentrated under reduced pressure, then treated with ice and water (50ml). The resulting mixture was extracted with ethyl acetate (100 ml),and the organic layer was washed with a saturated aqueous solution ofsodium bicarbonate (30 ml). The organic layer was dried over MgSO₄, thenevaporated under reduced pressure to give4-chloro-1H-pyrazolo[3,4-b]pyridine as a yellow solid (820 mg, 60%). ¹HNMR (300 MHz, CDCl₃) δ 8.57 (d, 1H, J=5.2 Hz), 8.25 (s, 1H), 7.28 (d,1H, J=5.2 Hz).

Example 52(b): ⁶-(⁷-azaindol-4-yl)-3-E-styryl-1H-indazole

[0912]

[0913] Sem-iodoindazole was converted to Example 52(b) in a similarmanner to that described for Example 27(a). ¹H NMR (300 MHz, MeOH-d4) δ8.40 (d, 1H, J=5.3 Hz), 8.53 (d, 1H, J=8.6 Hz), 7.74-7.35 (m, 10 H),6.90 (s, 1H). HRMS (FAB) [M+H]/z Calc'd 337.1448, found 337.1457.Analyzed with 0.3 H₂O, Calc'd, C (77.31), H (4.90), N (16.39). Found: C(77.51), H (4.88), N (16.27).

[0914] The starting material was prepared as follows:

[0915] 4Chloro-1H-pyrrolo[2,3-b]pyridine (Clark, B. A. et al., J. Chem.Soc. P1, 2270-74 (1974)) was converted to4-iodo-1H-pyrrolo[2,3-b]pyridine in a similar manner to that describedfor Example 52(a). ¹H NMR (300 MHz, MeOH-d4) δ 8.10 (m, 1H), 7.89 (d,1H, J=5.0 Hz), 7.58 (m, 1H), 7.50 (d, 1H, J=5.0 Hz), 6.26 (br s, 1H).

Example 53(a):3-(1H-benzoindazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0916]

[0917] To a solution of3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (208 mg, 0.7mmol) in dry dimethylformamide (6 mL) was added 4-aminophenol (82 mg,0.7 mmol) followed by HATU (312 mg, 0.8 mmol) and then triethylamine (20drops) was added. The reaction was stirred overnight at roomtemperature. LC/MS showed desired product as major component. Thesolvent was removed by vacuum. The residue remaining was taken up inwater and ethyl acetate. The layers were separated and the organic layerwas concentrated under vacuum. The residue was dissolved in methanol (10mL) and half of this solution was purified by HPLC using a gradient of5% acetonitrile/water to 55% acetonitrile/water over 60 minutes with0.1% trifluoroacetic acid in the water. The title compound was isolatedas a solid (20 mg). ¹H NMR (methanol-d₄) δ 6.87 (2H, d, 8.8 Hz), 7.55(2H, d, 8.7 Hz), 7.61 (2H, m), 7.87 (2H, br s), 8.00 (1H, d, 8.4 Hz),8.35 (1H, s), 8.52 (1H, d, 8.6 Hz). MS (APCI pos) 370.1.

[0918] The starting material was prepared as follows:

[0919] To 1H-indole-6-carboxylic acid (2.0 g, 12.42 mmol) in water (100mL) was added NaNO₂ (8.56 g, 124.2 mmol). To this suspension was thenslowly added dropwise via addition funnel 6N HCL (16mL). The resultingslurry was allowed to stir at room temperature overnight. The solidprecipitate was filtered and washed with water (SOmL) to provide 2.35 g(100%) of 3-formyl-1H-indazole-6-carboxylic acid. ¹H NMR (DMSO-d₆) δ14.46 (1H, s), 10.21 (1H, s), 8.26 (1H, s), 8.20 (1H, d, J=8.5 Hz), 7.90(1H, d, J=8.3 Hz). MS (APCI positive) 205 (methyl ester).

[0920] To 3-formyl-1H-indazole-6-carboxylic acid (2.35 g, 12.42 mmol) inDMF (60 mL) was added 1,2-phenylenediamine (12.42 mmol, 1.34 g) andsulfur powder (1.1 eq, 13.66 mmol). This mixture was then heated toreflux for 6 hours. The reaction was followed by TLC and LC-MS. Aftercooling, water (50 mL) was added to the reaction and the brownprecipitate which formed was filtered and collected to provide 3.1 g(90%) of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid. ¹H NMR(DMSO-d₆) δ 14.01 (1H, s), 8.58 (1H, d, J=8.5 Hz), 8.24 (1H, s), 7.87(1H, d, J=8.7 Hz), 7.64 (2H, m), 7.25 (2H, m). MS (APCI positive) 279.

Example 53(b):3-(1H-Benzoimidazol-2-yl)-N-cyclopropyl-1H-indazole-6-carboxamide

[0921]

[0922] To 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (200mg, 0.719 mmol) in DMF (30 mL) was added cyclopropylamine (98 mg, 0.719mmol), HATU (0.719 mmol, 273 mg), and triethylamine (0.726 mmol, 0.1mL). This solution was allowed to stir at room temperature overnight.The reaction was worked up via aqueous wash and extraction with ethylacetate (3×50 mL). The organic layer was then dried with MgSO₄, filteredand concentrated to yield a dark oil. Flash column chromatography(30-70% Ethyl Acetate/Petroleum Ether) afforded the3-(1H-benzoimidazol-2-yl)-N-cyclopropyl-1H-indazole-6-carboxamide as ayellow solid. (0.130 g, 57%) ¹H NMR (DMSO-d₆) δ 13.88 (1H, s), 8.63 (1H,m), 8.51 (1H, d, J=8.5 Hz), 8.09 (1H, s), 7.75 (1H, d, J=8.7 Hz), 7.63(2H, br s), 7.21 (2H, m), 2.89 (1H, m), 0.72 (2H, m), 0.63 (2H, m). MS(APCI positive) 318.1.

Example 53(c):3-(1H-benzoiniidazol-2-yl)-N-(4-hydroxy-3-methylphenyl)-1H-indazole-6-carboxamide

[0923]

[0924] Example 53(c) was prepared in a similar manner to that describedfor Example 53(a), except 3-methyl-4-aminophenol was used in place of4-aminophenol. ¹H NMR (DMSO-d₆) δ 8.59 (1H, d, J=8.3 Hz), 8.25 (1H, s),7.89 (1H, dd, J=1.3, 8.5 Hz), 7.68 (2H, br s), 7.28 (2H, m), 7.14 (1H,d, J=8.5 Hz), 6.74 (1H, s), 6.68 (2H, dd, J=3.0, 8.3 Hz). MS (APCIpositive) 384.1.

Example 53(d):3-(1H-benzoimidazol-2-yl)-N-(4hydroxy-2,3-dimethylphenyl)-1H-indazole-6-carboxamide

[0925]

[0926] Example 53(d) was prepared in a similar manner to that describedfor Example 15 53(a), except that 2,3-dimethyl-4-aminophenol was used inplace of 4-aminophenol. ¹H NMR (DMSO-d₆) δ 9.93 (1H, s), 9.22 (1H, s),8.56 (1H, d, J=8.5 Hz), 8.25 (1H, s), 7.90 (1H, d, J=8.5 Hz), 7.73 (1H,br s), 7.53 (1H, br s), 7.23 (2H, br s), 6.92 (1H, d, J=8.3 Hz), 6.68(1H, d, J=8.5 Hz), 2.09 (6H, br s). MS (APCI positive) 398.4.

Example 53(e): 3-(1H-Benzoomnidazol-2-yl)-1H-indazole-6-carboxamide

[0927]

[0928] Example 53(e) was prepared in a similar manner to that describedfor Example 53(a), except that 1,1,1,3,3,3-hexamethyldisilazane was usedin place of 4-aminophenol. ¹H NMR (DMSO-d₆) δ 13.91 (1H, s), 13.04 (1H,s), 8.52 (1H, d, J=8.3 Hz), 8.20 (1H, br s), 8.15 (1H, s), 7.81 (1H, d,J=7.7 Hz), 7.75 (1H, d, J=6.6 Hz), 7.51 (2H, m), 7.21 (2H, m). MS (APCIpositive) 278.1.

Example 53(f):3-(1H-benzoimidazol-2-yl)-N-benzyloxy-1H-indazole-6-carboxainde

[0929]

[0930] Example 53(f) was prepared in a similar manner to that describedfor Example 53(a) except that 0-benzylhydroxylamine was used in place of4-aminophenol. ¹H NMR (DMSO-d₆) δ 13.94 (1H, s), 13.06 (1H, s), 11.97(1H, s), 8.55 (1H, d, J=8.8 Hz), 8.02 (1H, s), 7.78 (1H, d, J=8.3 Hz),7.52 (1H, d, J=8.3 Hz), 7.50 (3H, m), 7.40 (3H, m), 7.22 (2H, m), 4.97(2H, s). MS (APCI positive) 384.2.

Example 53(g): 3-(1H-benzoimidaz1-2-yl)-N-(3-fluoro-4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0931]

[0932] Example 53(g) was prepared in a similar manner to that describedfor Example 53(a) except that 3-fluoro-4-aminophenol was used in placeof 4-aminophenol. ¹H NMR (CH₃OD) δ 8.58 (1H, d, J=8.5 Hz), 8.20 (1H, s),7.84 (1H, d, J=8.7 Hz), 7.68 (2H, br s), 7.63 (1H, dd, J=2.4, 13 Hz),7.29 (3H, m), 6.92 (1H, t, J=9.2 Hz). MS (APCI positive) 388.3.

Example 54(a):3-(5,6-Difluoro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0933]

[0934] Using the same procedure as for the synthesis of3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid in Example53(a), step (ii), N-(4-hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamideand 4,5-difluorol,2-phenylenediamine gave3-(5,6-difluoro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamideas a tan solid. ¹H NMR (DMSO-d₆) δ 13.99 (1H, s), 13.27 (1H, s), 10.21(1H, s), 9.25 (1H, s), 8.52 (1H, d, J=8.7 Hz), 8.21 (1H, s), 7.85 (1H,d, J=9.0 Hz), 7.80 (1H, t, J=9.8 Hz), 7.55 (2H, d, J=8.7 Hz), 7.47 (1H,t, J=9.8 Hz), 6.75 (2H, d, J=8.7 Hz). MS (APCI positive) 406. Thestarting material was prepared as follows:

[0935] To a solution of 3-formyl-1H-indazole-6-carboxylic acid (1.6 g,8.4 mmol) and 4-aminophenol (1.8 g, 16.8 mmol) in dry dimethylformamide(35 mL) was added HATU (3.8 g, 16.8 mmol) followed by triethylamine (1.4mL, 10.1 mmol). The reaction was stirred at room and monitored by TLCand LCIMS. After two hours the reaction was complete. The solvent wasremoved by vacuum and the product was purified by flash columnchromatography using ethyl acetate: petroleum ether 1:1 to pure ethylacetate. N-(4-Hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide wasisolated as a tan colored solid. ¹H NMR (DMSO-d₆) δ 6.79 (2H, d, 8.9Hz), 7.59 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz),8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.

Example 54(b):3-(5,6-Dichloro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0936]

[0937] Example 54(b) was prepared in a similar manner to that describedfor Example 54(a), except that 4,5-dichloro-1,2-phenylenediamine wasused in place of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (DMSO-d₆) 814.08 (1H, s), 13.38 (1H, s), 10.22 (1H, s), 9.27 (1H, s), 8.52 (1H, d,J=8.7 Hz), 8.23 (1H, s), 8.02 (1H, s), 7.86 (1H, d, J=8.7 Hz), 7.70 (1H,s), 7.55 (2H, d, J=8.7 Hz), 6.75 (2H, d, J=8.7 Hz). MS (APCI positive)438.

Example 54(c):3-(5-Methoxy-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0938]

[0939] Example 54(c) was prepared in a similar manner to that describedfor Example 54(a), except that 4-methoxy-1,2-phenylenediamine was usedin place of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (DMSO-d₆) δ 13.76(1H, s), 12.77 (1H, s), 10.13 (1H, s), 9.17 (1H, s), 8.45 (1H, d, J=8.3Hz), 8.11 (1H, s), 7.75 (1H, d, J=8.6 Hz), 7.46 (2H, d, J=8.7 Hz), 7.32(1H, d, J=8.3 Hz), 6.91 (1H, s), 6.77 (1H, m), 6.67 (2H, d, J=8.7 Hz),3.72 (3H, s). MS (APCI positive) 400.

Example 54(d):3-[1H-Naphtho(2,3-d)imidazol-2-yl]-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0940]

[0941] Example 54(d) was prepared in a similar manner to that describedfor Example 54(a), except that 2,3-naphthalenenediamine was used inplace of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (DMSO-d₆) δ 14.11(1H, s), 13.10 (1H, s), 10.24 (1H, s), 9.27 (1H, s), 8.64 (1H, d, J=8.7Hz), 8.28 (1H, s), 8.25 (1H, s), 7.97 (2H, m), 7.73 (1H, br s), 7.89(1H, d, J=8.6 Hz), 7.56 (2H, d, J=8.7 Hz), 7.38 (2H, b), 6.76 (2H, d,J=8.7 Hz). MS (APCI positive) 420.

Example 54(e):3-[1H-Naphtho(1,2-d)imidazol-2-yl]-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0942]

[0943] Example 54(e) was prepared in a similar manner to that describedfor Example 54(a), except that 1,2-naphthalenenediamine was used inplace of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (DMSO-d₆) δ 13.93(1H, s), 13.38 (1H, s), 10.23 (1H, s), 9.27 (1H, s), 8.70 (2H, m), 8.22(1H, s), 8.00 (1H, d, J=8.0 Hz), 7.87 (1H, m), 7.72 (3H, m), 7.57 (2H,d, J=8.7 Hz), 6.76 (2H, d, J=8.6 Hz). MS (APCI positive) 420.

Example 54(f):3-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0944]

[0945] Example 54(f) was prepared in a similar manner to that describedfor Example 54(a), except that 3,4-dimethyl-1,2-phenylenediamine wasused in place of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (DMSO-d₆) δ13.77 (1H, d, tautomers), 12.70 (1H, d, tautomers), 10.11 (1H, s), 9.16(1H, s), 8.48 (1H, d, J=8.3 Hz), 8.09 (1H, s), 7.73 (1H, d, J=8.6 Hz),7.47 (2H, d, J=8.7 Hz), 7.10 (1H, d, J=8.3 Hz), 6.93 (1H, d, J=8.3 Hz),6.65 (2H, d, J=8.7 Hz), 2.49 (3H, s), 2.24 (3H, s). MS (APCI positive)398.4.

Example 54(g):3-(5-tert-Butyl-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0946]

[0947] Example 54(g) was prepared in a similar manner to that describedfor Example 54(a), except that 4-tert-butyl-1,2-phenylenediarnine wasused in place of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (acetone-d₆)δ 12.88 (1H, s), 9.47 (1H, s), 8.63 (1H, d, J=8.7 Hz), 8.18 (1H, s),7.82 (1H, d, J=8.3 Hz), 7.57 (4H, m), 7.26 (1H, d, J=8.4 Hz), 6.74 (I H,d, J=8.3 Hz), 1.31 (9H, s). MS (APCI positive) 426.

Example 54(h):3-(5-Trifluoromethyl-1H-benzoimildazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0948]

[0949] Example 54(h) was prepared in a similar manner to that describedfor Example 54(a), except that 4-trifluoromethyl-1,2-phenylenediaminewas used in place of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR(methanol-d4) δ 6.86 (2H, d, 8.9 Hz), 7.54 (2H, d, 8.9 Hz), 7.6 (1H, dd,8.5 Hz), 7.83 (1H, d, 8.3 Hz), 7.89 (1H, dd, 8.6 Hz), 8.04 (1H, br s),8.25 (1H, s), 8.61 (1H, d, 8.6 Hz). MS (APCI pos) 438.1.

Example 54(i):3-(5-Fluoro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0950]

[0951] Example 54(i) was prepared in a similar manner to that describedfor Example 54(a), except that 4-fluoro-1,2-phenylenediamine was used inplace of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (acetone-d6) δ 13.40(1H, b), 12.47 (1H, b), 9.74 (1H, s), 8.67 (1H, d, J=8.6 Hz), 8.66 (1H,s), 8.29 (1H, s), 7.94 (1H, d, J=8.5 Hz), 7.67 (2H, J=8.4 Hz), 7.64 (1H,m), 7.40 (1H, m), 7.05 (1H, t, J=8.5 Hz), 6.83 (2H, d, J=8.4 Hz). MS(APCI pos) 388.

Example 54(j):3-(5H-[1,3]dioxolo[4,5-f]benzoimidazol-6-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0952]

[0953] Example 54(j) was prepared in a similar manner to that describedfor Example 54(a), except that 4,5-methylenedioxy-1,2-phenylenediaminewas used in place of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR(methanol-d4) δ 6.85 (2H, d, 8.9 Hz), 7.15 (2H, s), 7.54 (2H, d, 8.9Hz), 7.86 (1H, dd, 8.6 Hz), 8.23 (1H, s), 8.55 (1H, dd, 8.5 Hz). MS(APCI pos) 414.1.

Example 54(k):3-(5,6-Dimethoxy-1H-benzoinidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0954]

[0955] Example 54(k) was prepared in a similar manner to that describedfor Example 54(a), except that 4,5-dimethoxy-1,2-phenylenediamine wasused in place of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (methanol-d4)δ 3.98 (6H, s), 6.85 (2H, d, 8.78 Hz), 7.29 (2H, br s), 7.54 (2H, d,8.73 Hz), 7.86 (1H, d, 8.57 Hz), 8.24 (1H, s), 8.57 (1H, d, 8.58 Hz). MS(APCI pos) 430.1.

Example 54(1):3-(5-Chloro-1H-benzoinidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

[0956]

[0957] Example 54(l) was prepared in a similar manner to that describedfor Example 54(a), except that 4-chloro-1,2-phenylenediamine was used inplace of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (methanol-d4) 8.62(1H, d, J=8.6 Hz), 8.30 (1H, s), 7.90 (1H, dd, J1=8.6 Hz, J2=1.3 Hz),7.69 (b, 2H), 7.56 (2H, d, J=6.89 Hz), 7.33 (1H, dd, J1=8.59, J2=1.97Hz), 6.88 (2H, d, J=6.89 Hz). MS (APCI pos) 404.1.

Example 55: 3-1H-Benzoinidazol-2-yl-6-pyridin-4-yl-1H-indazole

[0958]

[0959] Sem-Example 55 was converted to Example 55 in a similar manner tothat described for Example 27(a). ¹H NMR (300 MHz, CDCl₃ +MeOH-d4+DMSO-d₆) δ 8.71-8.64 (m, 3H), 8.03 (s, 1H), 7.86 (dd, 2H, J=4.7, 1.6Hz), 7.77-7.72 (m, 3H), 7.32 (dd, 2H, J=6.0, 3.1 Hz). HRMS (FAB) [M+H]/zCalc'd 312.1244, found 312.1253. Analyzed with 1.40 H₂O, Calc'd, C(67.80), H (4.73), N (20.81). Found: C (68.06), H (4.45), N (20.68).

[0960] The starting material was prepared as follows:

[0961] A solution of6-pyridin-4yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde(0.70 g, 2.0 mmol), benzene-1,2-diamine (0.26 g, 2.4 mmol) and sulfur(77 mg, 2.4 mmol) in DMF (10 ml) was heated in an oil bath at 90° C.overnight. The resulting mixture was poured into brine (200 ml), thenextracted with EtOAc (3×60 ml). The combined organic layer was driedover MgSO₄ and concentrated under reduced pressure. The resulting oilwas purified by silica gel chromatography to yield6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazoleas a light brown oil (0.75 g, 65%). ¹H NMR (CDCl₃) δ 8.82 (d, 1H, J=8.5Hz), 8.73 (d, 1H, J=5.8 Hz), 7.94-7.89 (m, 2H), 7.87 (s, 1H), 7.69-7.62(m, 4H), 7.40-7.34 (m, 2H), 3.70-3.49 (m, 4H), 0.94 (t, 2H, J=8.3 Hz),0.67 (t, 2H, J=8.2 Hz), −0.03 (s, 9H), -0. 13 (s, 9H).

Example 56:6-[3-(Propyn-³-ylcarbamoyl)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0962]

[0963] A solution of2-{1-[3-((E)-2-Pyrridin-2-yl-vinyl)-1H-indazol-6-yl]-methanoyl)1-benzoicacid (55.4 mg, 0.15 mmol) (synthesis described below), propargyl amine(15.4 μL, 0.225 mmol), and triethyl amine (41.8 μL, 0.30 mmol),dissolved in DMF (1.5 mL), was treated withO-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluroniumhexafluoro-phosphate (62.7 mg, 0. 165 mmol). After stirring for one hourthe mixture was concentrated under high vacuum and purified bypreparative C 18 reverse phase column chromatography. The resulting 40mg of product was further purified by “chromatotron” radialchromatography eluted with 25% CH₃CN/CH₂Cl₂, giving 16.5 mg of theproduct as a white solid (27% yield). ¹H NMR (DMSO-d₆) δ 13.30 (s, 1H),8.58 (d, J=5.00 Hz, 1H), 8.05 (d, J=8.29 Hz, 1H), 7.92 (d, J=16.2 Hz,1H), 7.79 (m, 3H), 7.63 (d, J=8.25 Hz, 1H) 7.5 3 (m, 3H), 7.32 (s, 1H),7.27 (m, 2H), 6.89 (d, J=8.48 Hz, 1H). Anal. Calcd. for C₂₅H₁₈N₄O₂.0.5H₂O: C, 72.27; H, 4.6 1; N, 13.49. Found: C, 72.39; H, 4.62; N, 13.69.

[0964] Synthesis of 2-{1-[3-((E)-2-Pyridin-2-yl-vinyl)- lH-indazol-6-yl]-methanoyl)-benzoic acid. A solution of2-{1-[3-((E)-2-Pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yl]-methanoyl}-benzoicacid (402 mg, 0.805 mmol) (synthesis described below), ethylene diamine(215 μL, 3.22 mmol), and 1M TBAF in THF (6.44 ml, 6.44 mmol), wasstirred in a 90° C. oil bath for 4 hr. The crude reaction mixture wasquenched with acetic acid (386 μL, 6.44 mmol), diluted with ethylacetate (100 mL), extracted 1M sodium bicarbonate solution (2×20 ml),brine (5×20 ml), dried magnesium sulfate, filtered, and concentrated toa 3 mL volume. The resulting crude material was purified by preparativeC 18 reverse phase column chromatography, giving 211 mg of the titlecompound as a yellow solid (71% yield). ¹H NMR (DMSO-d₆)δ 13.50(bs,1H),8.68(d, J=5.27 Hz, 1H),8.29(d, J=8.86 Hz, 1H),8.13-7.90 (m, 4H),7.81-7.43 (m, 7H).

[0965] Synthesis of2-(1-[3-((E)-2-Pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yl]-methanoyl}-benzoicacid. A solution 6-iodoindazole (477 mg, 1.0 mmol) dissolved in THF (10mL), at −100° C. was treated dropwise with 2.5 M n-butyl lithium inhexanes (440 μl, 1.10 mmol), stirred for 5 minutes at this temperature,then treated with a solution pthalic anhydride (222 mg, 1.5 mmol) in THF(1.0 mL). The resulting mixture was allowed to slowly warm to roomtemperature, where it was stripped of THF, diluted with ethyl acetate,extracted with 1 N citric acid, extracted with brine, dried overmagnesium sulfate, and concentrated to an oil. The oil was trituratedwith methylene chloride, and diethyl ether, giving 484 mg (81% yield) ofthe title compound as a white solid. ¹H NMR (DMSO-d₆) δ 8.67 (d, J=5.09Hz, 1H), 8.31 (d, J=8.85 Hz, 1H), 8.08-7.55 (m, 4H), 7.50-7.37 (m, 2H),5.81 (s, 2H), 3.53 (t, J=8.10 Hz, 2H), 0.78 (t, J=8.15 Hz, 2H), −0.12(s, 9H).

Example 57:6-[3-((1,3-dhnethyl-1H-pyrazol-5-yl)carboxaniido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

[0966]

[0967] Example 57 was prepared in a similar manner to that of Example58. ¹H NMR (300 MHz, DMSO-d₄) δ 13.15 (s, 1H), 10.17 (s, 1H), 8.60 (d,1H, J=4.2 Hz), 8.22 (d, 1H, J=8.7 Hz), 7.94 (d, 1H, J=16.4 Hz),7.84-7.79 (m, 1 H), 7.68-7.50 (m, 4H), 7.40 (t, 1H,J=8.1 Hz),7.30-7.26(m, 1H),7.06(s, 1H),7.00 (dd, 1H,J=8.8, 1.9 Hz),6.87 (dd, 1H,J=8.0, 1.9 Hz), 6.79 (s, 1H), 3.96 (s, 3H), 2.17 (s, 3H); ESIMS m/z 451[M+H]⁺. Anal. calcd for C₂₆H₂₂N₆O₂×0.5 H₂O×0.4 hexanes (494.0 g/mol): C,69.05; H, 5.84; N, 17.01. Found: C, 68.78; H, 5.55; N, 17.05.

Example 58:6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(1H-imidazol-2-yl)ethenyl]-1H-indazole

[0968]

[0969] A solution of tetrabutylammonium fluoride (7.5 mL, 1.0 M in THF,7.5 mmol, 15.0 eq) and 1,2-diaminoethane (0.33 mL, 5.0 mmol, 10 eq) wasadded to 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid[2-methyl-5-(1-(2-trimethylsilanyl-ethoxymethyl)-3-(E)-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-vinyl}-1H-indazol-6-yloxy)-phenyl]-amide(360 mg, 0.5 mmol, 1.0 eq) in 1,4-dioxane (5 mL) and the reactionmixture was heated to 90° C. for 18 hours. At the end of this time thereaction was concentrated under reduced pressure and the resultantorange oil was diluted with ethyl acetate (50 mL). The organic layer wasvigorously washed with saturated sodium bicarbonate (5×50 mL), brine,dried over magnesium sulfate and concentrated under reduced pressure togive a yellow solid (287 mg). The crude product was purified by radialchromatography on silica gel using 5% methanol-chloroform with 0.1%ammonium hydroxide (R_(f)0.1) as the eluant to give2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid(5-{3-[(E)-2-(1H-imidazol-2-yl)-vinyl]-1H-indazol-6-yloxy}-2-methyl-phenyl)-amide(140 mg, 61%) as a light yellow solid: HPLC R_(f)=11.8 min.; TLC Rf=0.8(10% methanol-chloroform with 0.1% ammonium hydroxide); ¹H NMR (300 MHz,DMSO-d₆) δ 13.03 (s, 1H), 12.30 (br. s, 1H), 9.78 (s, 1H), 8.00 (d, 1H,J=8.6 Hz), 7.54 (d, 1H, J=16.8 Hz), 7.32 (d, 1H, J=8.5 Hz), 7.27 (d, 1H,J=16.9 Hz), 7.13-7.12 (m, 3H), 7.00-6.94 (m, 3H), 6.78 (s, 1H), 4.39 (q,2H, J=7.1 Hz), 2.23 (s, 3H), 2.19 (s, 3H), 1.28 (t, 3H, J=7.1 Hz). Anal.calcd for C₂₆H₂₅N₇O₂×0.5 H₂O ×0.4 hexanes (511.0 g/mol): C, 66.75; H,6.23; N, 19.19. Found: C, 66.95; H, 6.25; N, 18.83.

[0970] The starting materials were prepared as follows:

[0971] (i) Preparation of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole

[0972] 1H-Imidazole (2.0 g, 29.4 mmol, 1.0 eq) in THF (70 mL) was addedto a 0° C. suspension of sodium hydride (1.5 g, 60% in mineral oil, 38.2mmol, 1.3 eq) in THF (30 mL). After gas evolution ceased, the mixturewas warmed to room temperature for 45 minutes and then recooled to 0° C.[2-(Trimethylsilyl)ethoxy]methyl chloride (5.4 mL, 30.2 mmol, 1.0 eq)was added, and the mixture was warmed to room temperature overnighl Thereaction was quenched with saturated sodium bicarbonate, the ThF removedunder reduced pressure, and the resultant beige slurry extracted withethyl acetate. The extracts were combined, washed with brine, dried overmagnesium sulfate, filtered, and concentrated to give 6.9 g of an amberoil. The oil was purified by flash chromatography on silica gel using 2%methanol-chloroform as the eluant to give1-(²-trimethylsilanyl-ethoxymethyl)-1H-imidazole as a light amber oil(4.7 g, 81%): TLC R_(f)=0.3 (5% methanol-chloroform); ¹H NMR (300 MHz,DMSO-d₆) δ 7.77 (s, 1H), 7.26 (d, 1H, J=1.2 Hz), 6.93 (s, 1H), 5.32 (s,2H), 3.45 (t, 2H, J=8.0 Hz), 0.83 (t, 2H, J=8.0 Hz), −0.05 (s, 9H); 1³CNMR (75 MHz, DMSO-d₆) δ 137.9, 128.8, 119.6, 74.8, 65.1, 17.1, −1.4.

[0973] (ii) Preparation of[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol

[0974] 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole (3.0 g, 15.4mmol, 1.0 eq) was dissolved in THF (150 mL) and cooled to −78° C. nBuLi(10.6 mL, 1.6 M in hexanes, 16.9 mmol, 1.1 eq) was added and thetemperature was allowed to increase to −40° C. over 15 minutes. Thelight yellow solution was stirred for an additional 30 minutes at −40°C. then the anion was quenched with DMF (1.3 mL, 16.9 mmol, 1.1 eq). Thereaction mixture was warmed to room temperature overnight then quenchedwith water. The solvent was removed and the mixture was extracted withdichloromethane. The organic layer was washed with water, dried withbrine and magnesium sulfate, filtered and concentrated to give the crudeproduct (3.5 g; TLC R_(f)=0.5 (5% methanol-chloroform). The proton NMRspectrum gives the aldehydic proton at 9.73 ppm (300 MHz, DMSO-d₆). Thecrude product was dissolved in methanol (15 mL), cooled to 0° C., andtreated with sodium borohydride (1.2 g, 30.8 mmol, 2.0 eq). The reactionmixture was warmed to room temperature overnight. The solvent wasremoved and the crude product was diluted with chloroform, washed withwater, dried with brine and magnesium sulfate, filtered and concentratedto give a clear oil (3.6 g). The oil was purified by flashchromatography on silica gel using 3-6% methanol-chloroform with 0.1%ammonium hydroxide as the eluant to give[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol as awhite solid (1.4 g, 41% 2-steps): TLC Rf=0.4 (8% methanol-chloroform);¹H NMR (300 MHz, DMSO-d₆) δ 7.22 (d, 1H, J=1.1 Hz), 6.81 (d, 1H, J=1.0Hz), 5.36 (s, 2H),5.31 (br. t, 1H, J=5.2 Hz), 4.50 (d, 2H, J=4.8 Hz),3.48 (t, 2H, J=8.0 Hz), 0.83 (t, 2H, J=8.0 Hz), −0.05 (s, 9H); ¹³C NMR(75 MHz, DMSO-d₆) δ 148.9, 127.8, 122.5, 75.5, 66.5, 56.9, 18.5, 0.0.

[0975] (iii) Preparation of2-chloromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazolehydrochloride

[0976] A solution of thionyl chloride (0.87 mL, 12.0 mmol, 3.0 eq) inchloroform (8 mL) was cooled to 0° C. and treated with a solution of[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol (0.92 g,4.0 mmol, 1.0 eq) in chloroform (2 mL). The clear solution was stirredat 0° C. for 30 minutes and then at room temperature for 2 hours. Thesolvent was removed and the product was sequentially slurried andconcentrated using chloroform, toluene and cyclohexane to give2-chloromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazolehydrochloride as a beige solid (1.1 g, 97%): ¹H NMR (300 MHz, DMSO-d₆) δ7.85 (d, 1H, J=1.9 Hz), 7.70 (d, 1 H, J=1.9 Hz), 5.62 (s, 2H), 5.14 (s,2H), 3.57 (t, 2H, J=8.3 Hz), 0.90 (t, 2H, J=8.3 Hz), −0.02 (s, 9H); ¹³CNMR (75 MHz, DMSO-d₆) δ 142.1, 123.2, 120.2, 76.5, 66.8, 31.7, 17.3,−1.4.

[0977] (iv) Preparation of 3-amino-4-methyl-phenol

[0978] Black solid (95%); HPLC R_(f)=4.4 min.; ¹H NMR (300 MHz, DMSO-d₆)δ 8.61 (s, 1H), 6.64 (d, 1H, J=8.1 Hz), 6.05 (d, 1H, J=2.4 Hz), 5.88(dd, 1H, J=8.0, 2.4 Hz), 8 mol %) andbiphenyl-2-yl-di-tert-butyl-phosphane (656 mg, 2.2 mmol, 16 mol %). Theflask was immersed in an oil bath and stirred at 100° C. for 18 hours.The black slurry was cooled to room temperature, filtered through celiteand concentrated. The black oil was dissolved in chloroform, washed withwater, brine, dried over magnesium sulfate, filtered and concentrated togive a black oil (12.1 g). The crude product was purified by flashchromatography on silica gel using 10-15% ether-cyclohexane as theeluant togive-benzhydrylidene-(2-methyl-5-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-phenyl}-amineas a yellow foam from ether (1.4 g, 16%): HPLC R_(f)=24.3 min.; TLCRf=0.5 (20% ether-cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (d, 1H,J=8.8 Hz), 7.75-7.66 (m, 4H), 7.53-7.31 (m, 1H), 7.14-7.08 (m, 4H), 6.62(dd, 1H, J=8.8, 2.0 Hz), 6.55 (dd, 1H, J=8.2, 2.5 Hz), 6.20 (d, 1H,J=2.4 Hz), 5.64 (s, 2H), 3.51 (t, 2H, J=7.8 Hz), 2.12 (s, 3H), 0.78 (t,2H, J=7.7 Hz), 4).14 (s, 9H).

[0979] (vii) Preparation of2-methyl-5-r3-((E)-stvryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxyl-phenylamine

[0980] Amber oil (80%); HPLC R_(f)=21.0 min.; TLC R_(f)=0.4 (20% ethylacetate-cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (d, 1H, J=8.8Hz), 7.74-7.71 (m, 2H), 7.52 (s, 2H), 7.43-7.38 (m, 2H), 7.33-7.28 (m,1H), 7.20 (d, 1H, J=2.0 Hz), 6.97-6.90 (m, 2H), 6.33 (d, 1H, J=2.4 Hz),6.16 (dd, 1H, J=8.0, 2.5 Hz), 5.66 (s, 2H), 5.01 (br. s, 2H), 3.52 (t,2H, J=8.0 Hz), 2.03 (s, 3H), 0.80 (t, 2H, J=8.0 Hz), −0.11 (s, 9H).

[0981] (viii) Preparation of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylicacid{2-methyl-5-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-phenyl)-amide

[0982] White foam (85%); HPLC R_(f)=21.5 min.; TLC Rf=0.2 (20% ethylacetate-cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ 9.75 (s, 1H), 8.24 (d,1H, J=8.8 Hz), 7.74-7.72 (m, 2H), 7.53 (s, 2H), 7.43-7.38 (m, 2H),7.34-7.28 (m, 3H), 7.12 (d, 1H, J=2.6 Hz), 7.00 (dd, 1H, J=8.8, 2.0 Hz),6.92 (dd, 1H, J=8.3, 2.5 Hz), 6.78 (s, 1H), 5.69 (s, 2H), 4.40 (q, 2H,J=7.1 Hz), 3.53 (t, 2H, J=7.9 Hz), 2.22 (s, 3H), 2.19 (s, 3H), 1.27 (t,3H, J=7.1 Hz), 0.78 (t, 2H, J=7.9 Hz), -0.15 (s, 9H).

[0983] (ix) Preparation of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylicacid[5-3-formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-2-methyl-Dhenyl}-amide

[0984] A solution of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid{2-methyl-5-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-phenyl}-amide(774 mg, 1.28 mmol, 1.0 eq) in 1,4-dioxane (8 mL) and water (2 mL) wastreated with osmium tetraoxide (7 mg, 0.03 mmol, 0.02 eq). The solutionwas stirred for 5 minutes then treated with sodium periodate (822 mg,3.84 mmol, 3.0 eq). The resultant thick tan slurry was stirred at roomtemperature overnight, poured into 15% Na₂S₂O₃ (100 mL) and extractedwith ethyl acetate. The organic layer was washed with saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to give an amber oil (902 mg). The crude product waspurified by radial chromatography on silica gel using 10-50% ethylacetate-cyclohexane as the eluant to give2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid(5-[3-formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-2-methyl-phenyl}-amideas a beige solid from ether (590 mg, 86%): HPLC R_(f)=18.9 min.; TLCR_(f)=0.2 (40% ethyl acetate-cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ10.16 (s, 1H), 9.75 (s, 1H), 8.14 (d, 1H, J=8.8 Hz), 7.48 (d, 1H, J=1.8Hz), 7.32 (d, 1H, J=8.5 Hz), 7.16-7.13 (m, 2H), 6.93 (dd, 1H, J=8.3, 2.6Hz), 6.78 (s, 1H), 5.84 (s, 2H), 4.39 (q, 2H, J=7.1 Hz), 3.55 (t, 2H,J=7.8 Hz), 2.23 (s, 3H), 2.19 (s, 3H), 1.27 (t, 3H, J=7.2 Hz), 0.79 (t,2H, J=7.8 Hz), -0.15 (s, 9H).

[0985] (x) Preparation of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid[2-methyl-5-(1-(2-trimethylsilanyl-ethoxymethyl)-3-{(E)-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-vinyl}-1H-indazol-6-yloxy)-phenyl]-amide

[0986] A solution of2-chloromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazolehydrochloride (344 mg, 1.22 mmol, 2.0 eq) in chloroform (20 mL) was freebased with saturated sodium bicarbonate. The organic layer was driedwith brine and magnesium sulfate, filtered and concentrated to give anamber oil (301 mg, 100%). The resultant oil was dissolved inacetonitrile (12 mL), treated with triphenylphosphine (304 mg, 1.16mmol, 1.9 eq) and warmed to 70° C. for 18 hours. The solvent was removedand the crude1-(2-trimethylsilanyl-ethoxymethyl)-2-[(triphenyl-λ⁵-phosphanyl)-methyl]-1H-imidazolechloride was dissolved in THF (12 mL), cooled to −78° C., and treatedwith potassium tert-butoxide (1.2 mL, 1.0 M in THF, 1.22 mmol, 2.0 eq).After 15 minutes, 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid{5-[3-formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-2-methyl-phenyl}-amide(325 mg, 0.61 mmol, 1.0 eq) in THF (1 mL) was added to the ylide at −78°C. The clear yellow solution was warmed to room temperature overnight,quenched with water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over magnesium sulfate, filtered andconcentrated to give the crude product as an amber oil (1.0 g). Thecrude product was purified further by radial chromatography on silicagel using 0-5% methanol-chloroform as the eluant to give2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid[2-methyl-5-(1-(2-trimethylsilanyl-ethoxymethyl)-3-{(E)-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-vinyl}-1H-indazol-6-yloxy)-phenyl]-amide as a tan solid upon standingovernight (390 mg, 88%); HPLC R_(f)=20.6 min.; TLC R_(f)=0.4 (4%methanol-dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ 9.75 (s, 1H),8.14 (d, 1H, J=8.8 Hz), 7.64 (d, 1H, J=16.2 Hz), 7.42 (d, 1H, J=16.3Hz), 7.39-7.35 (m, 3H), 7.30 (d, 1H,J=8.5 Hz), 7.12 (d, 1H,J=2.5 Hz),7.03 (s, 1H), 6.99 (dd, 1H, J=8.8, 1.9 Hz), 6.78 (s, 1H), 5.70 (s, 2H),5.55 (s, 2H), 4.40 (q, 2H, J=7.1 Hz), 3.55-3.48 (m, 4H), 2.22 (s, 3H),2.19 (s, 3H), 1.27 (t, 3H, J=7.1 Hz), 0.84 (t, 2H, J=7.9 Hz), 0.77 (t,2H, J=7.9 Hz), -0.11 (s, 9H), -0.15 (s, 9H). cl Example 59(a):6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazolehydrochloride

[0987] Example 41(a) (4.57 g, 9.59 mmol, 1 equiv) was taken up inmethanol (96 mL) and was protected from light with aluminum foil. Asecond flask with methanol (20 mL) was treated with acetyl chloride (684ILL, 1.00 equiv) for 5 min. The acid solution was then added to thefirst mixture with several methanol washes (˜20 mL). The volatilematerial was removed under reduced pressure and the residue wastriturated with 1:1 ethyl acetate-hexane to give, after filtering anddrying, a yellow powder (4.82 g, 98%): Analyzed with 1.0 H₂O Calc'd, C(61.85), H (5.07), N (15.46). Found: C (61.15), H (5.15), N (15.38).

Example 59(b):6-[3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazolehydrochloride

[0988]

[0989] Example 59(b) was prepared in similar manner as Example 59(a)except that Example 41(p) was used in place of Example 41(a). HPLC: 3.92min (100% area); ¹H NMR (DMSO) δ 10.45 (s, 1H), 8.85 (d, 1H, J=4.8 Hz),8.49 (d, 1H, J=8.7 Hz), 8.38-8.30 (m, 4H), 8.21 (dt, 1H, J=7.5, 2.1 Hz),8.01(s, 1H), 7.90-7.79 (m, 2H), 7.72-7.64 (m, 3H), 6.70 (s, 1H), 4.10(s, 3H), 2.33 (s, 3H). Anal. (C₂₇H₂₀N₄O₂S1.3 H₂O, 0.2EtOAc): Calc. C,62.15; H, 5.18; N, 15.64. Found C, 61.81; H, 5.01; N, 15.64.

Example 59(c):6-[N-(5((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)-2-fluoro-4-methylphenyl)amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazolehydrochloride

[0990]

[0991] Example 59(c) was prepared in similar manner as Example 59(a)except that Example 48(a) was used in place of Example 41(a). Anal.Calc'd: C, 63.21; H, 5.12; N, 18.43; Cl, 6.66. Found: C, 60.86; H, 5.38;N, 17.28: Cl, 6.52. Example 59(d):6-[N-(3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)-4-fluoro-phenyl)amino]-3-E-[2-(pyridin.2-yl)ethenyl]-1H-indazolehydrochloride

[0992] Example 59(d) was prepared in similar manner as Example 59(a)except that Example 49(a) was used in place of Example 41(a). ¹H NMR(300 MHz, DMSO-d₆) δ 13.2 (b, 1H), 9.97 (s, 1H), 8.75 (d, 1H, J=5.44Hz), 8.51 (bs, 1H), 8.35 (m, 2H), 8.20 (d, 1H, J=16.59 Hz), 8.06 (d, 1H,J=8.81 Hz), 7.71 (d, 1H, J=16.59 Hz), 7.70 (m, 1H), 7.44 (dd, 1H, J=6.65Hz, J=2.67 Hz), 7.24 (t, 1H, J=9.54 Hz), 7.12 (d, 1H, J=1.46 Hz), 7.05(m, 2H), 6.86 (s, 1H), 4.0 (s, 3H), 3.84 (bs, 1H), 2.20 (s, 3H).

Example 59(e):6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazolehydrochloride

[0993]

[0994] Example 59(e) was prepared in similar manner as Example 59(a)except that Example 31(d) was used in place of Example 41(a). ¹H NMR(DMSO-d₆) δ 13.53 (s, 1H), 10.23 (s, 1H) 8.78 (d, 1H, J=5.5 Hz), 8.30(m, 4H), 7.80 (m, 2H), 7.59 (d, 1H J=7.7 Hz), 7.55 (s, 1H), 7.41 (t, 1H,J=8.1 Hz), 7.11 (s, 2H), 6.88 (d, 1H, J=6.7 Hz), 6.81 (s, 1H), 4.38(q,2H, J=7.0 Hz), 3.75 (bs, 1H), 2.19 (s, 3H), 1.29 (t, 3H, J=7.0 Hz).Anal. Calc for C₂₇H25CIN₆02-1.7 H₂O 0.1 EtOAc: C, 60.89; H, 5.45; N,15.55. Found: C, 60.88; H, 5.51; N, 15.27.

Example 59(f):6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazolehydrochloride

[0995]

[0996] Example 59(f) was prepared in similar manner as Example 59(a)except that Example 33(a) was used in place of Example 41(a). Analyzedwith 2.0 H₂O Calc'd C, 57.58; H, 5.05; N, 12.21; Cl, 6.99. Found: C,57.24; H, 5.048; N, 11.91: Cl, 6.63.

[0997] The exemplary compounds described above may be tested for theiractivity using the tests described below.

Biological Testing: Enzyme Assays

[0998] The stimulation of cell proliferation by growth factors such asVEFG, FGF, and others is dependent upon their induction ofautophosphorylation of each of their respective receptor's tyrosinekinases. Therefore, the ability of a protein kinase inhibitor to blockautophosphorylation can be measured by inhibition of the peptidesubstrates. To measure the protein kinase inhibition activity of thecompounds, the following constructs were devised.

[0999] VEGF-R2 Construct for Assav: This construct determines theability of a test compound to inhibit tyrosine kinase activity. Aconstruct (VEGF-R2Δ50) of the cytosolic domain of human vascularendothelial growth factor receptor 2 (VEGF-R2) lacking the 50 centralresidues of the 68 residues of the kinase insert domain was expressed ina baculovirus/insect cell system. Of the 1356 residues of full-lengthVEGF-R2, VEGF-R2Δ50 contains residues 806-939 and 990-1171, and also onepoint mutation (E99OV) within the kinase insert domain relative towild-type VEGF-R2. Autophosphorylation of the purified construct wasperformed by incubation of the enzyme at a concentration of 4 μM in thepresence of 3 mM ATP and 40 mM MgCl₂ in 100 mM HEPES, pH 7.5, containing5% glycerol and 5 mM DTT, at 4° C. for 2 h. After autophosphorylation,this construct has been shown to possess catalytic activity essentiallyequivalent to the wild-type autophosphorylated kinase domain construct.See Parast et al., Biochemistry, 37, 16788-16801 (1998).

[1000] FGF-R 1 Construct for Assay: The intracellular kinase domain ofhuman FGF-R1 was expressed using the baculovirus vector expressionsystem starting from the endogenous methionine residue 456 to glutamate766, according to the residue numbering system of Mohammadi et al., Mol.Cell. Biol., 16, 977-989 (1996). In addition, the construct also has thefollowing 3 amino acid substitutions: L457V, C488A, and C584S.

[1001] LCK Construct for Assay: The LCK tyrosine kinase was expressed ininsect cells as an N-terminal deletion starting from amino acid residue223 to the end of the protein at residue 509, with the following twoamino acid substitutions at the N-terminus: P233M and C224D.

[1002] CHK1 Construct for Assav: C-terminally His-tagged full-lengthhuman CHK1 (FL-CHK1) was expressed using the baculovirus/insect cellsystem. It contains 6 histidine residues (6 x His-tag) at the C-terminusof the 476 amino acid human CHK1. The protein was purified byconventional chromatographic techniques.

[1003] CDK2/Cyclin A Construct for Assay: CDK2 was purified usingpublished methodology (Rosenblatt et al., J. Mol. Biol., 230, 1317-1319(1993)) from insect cells that had been infected with a baculovirusexpression vector. Cyclin A was purified from E. coli cells expressingfull-length recombinant cyclin A, and a truncated cyclin A construct wasgenerated by limited proteolysis and purified as described previously(Jeffrey et al., Nature, 376, 313-320 (1995)).

[1004] CDK4/Cyclin D Construct for Assay: A complex of human CDK4 andcyclin D3, or a complex of cyclin D1 and a fusion protein of human CDK4and glutathione-S-transferase (GST-CDK4), was purified using traditionalbiochemical chromatographic techniques from insect cells that had beenco-infected with the corresponding baculovirus expression vectors.

[1005] FAK Construct for Assay. The catalytic domain of human FAK(FAKcd4O9) was expressed using the baculovirus vector expression system.The 280 amino acid domain expressed comprises residues methionine 409 toglutamate 689. One amino acid substitution exists (P410T) relative tothe sequence assession number L13616 published by Whithey, G. S. et al.,DNA Cell Biol, 9, 823-30 (1993). The protein was purified usingclassical chromatography techniques.

[1006] TIE-2 (TEK) Construct for Assay

[1007] The TIE-2 tyrosine kinase domain was expressed in insect cells asan N-terninal deletion starting from amino acid residue 774 to the endof the protein at residue 1124. This construct also carries a R774Mmutation, which serves as the initiating methionine residue intranslation.

[1008] VEGF-R2 Assay

[1009] Coupled Spectrophotometric (FLVK-P) Assay

[1010] The production of ADP from ATP that accompanies phosphoryltransfer was coupled to oxidation of NADH using phosphoenolpyruvate(PEP) and a system having pyruvate kinase (PK) and lactic dehydrogenase(LDH). The oxidation of NADH was monitored by following the decrease ofabsorbance at 340 nm (e₃₄₀=6.22 cm⁻¹ mM⁻¹) using a Beckman DU 650spectrophotometer. Assay conditions for phosphorylated VEGF-R2A50(indicated as FLVK-P in the tables below) were the following: 1 mM PEP;250 μM NADH; 50 units of LDH/mL; 20 units of PK/mL; 5 mM DTT; 5.1 mMpoly(E₄Y₁); 1 mM ATP; and 25 mM MgCl₂ in 200 mM HEPES, pH 7.5. Assayconditions for unphosphorylated VEGF-R2Δ50 (indicated as FLVK in thetables) were the following: 1 mM PEP; 250 μM NADH; 50 units of LDH/mL;20 units of PK/mL; 5 mM DTT; 20 mM poly(E₄Y₁); 3 mM ATP; and 60 mM MgCl₂and 2 mM MnClin 200 mM HEPES, pH 7.5. Assays were initiated with 5 to 40nM of enzyme. K_(i) values were determined by measuring enzyme activityin the presence of varying concentrations of test compounds. The datawere analyzed using Enzyme Kinetic and Kaleidagraph software.

[1011] ELISA Assay

[1012] Formation of phosphogastrin was monitored using biotinylatedgastrin peptide (1-17) as substrate. Biotinylated phosphogastrin wasimmobilized using streptavidin coated 96-well microtiter plates followedby detection using anti-phosphotyrosine-antibody conjugated tohorseradish peroxidase. The activity of horseradish peroxidase wasmonitored using 2,2′-azino-di-[3-ethylbenzathiazoline sulfonate(6)]diammonium salt (ABTS). Typical assay solutions contained: 2 μMbiotinylated gastrin peptide; 5 mM DTT; 20 μM ATP; 26 mM MgCl₂; and 2 mMMnCl₂ in 200 mM HEPES, pH 7.5. The assay was initiated with 0.8 nM ofphosphorylated VEGF-R2A50. Horseradish peroxidase activity was assayedusing ABTS, 10 mM. The horseradish peroxidase reaction was quenched byaddition of acid (H₂SO₄), followed by absorbance reading at 405 nm.K_(i) values were determined by measuring enzyme activity in thepresence of varying concentrations of test compounds. The data wereanalyzed using Enzyme Kinetic and Kaleidagraph software. FGF-R Assay

[1013] The spectrophotometric assay was carried out as described abovefor VEGF-R2, except for the following changes in concentration: FGF-R=50nM, ATP=2 mM, and poly(E4Y1)=15 mM.

[1014] LCK Assay

[1015] The spectrophotometric assay was carried out as described abovefor VEGF-R2, except for the following changes in concentration: LCK=60nM, MgCl₂=0 mM, poly(E4Y1)=20 mM.

[1016] CHK1 Assay

[1017] The production of ADP from ATP that accompanies phosphoryltransfer to the synthetic substrate peptide Syntide-2 (PLARTLSVAGLPGKK)was coupled to oxidation of NADH using phosphoenolpyruvate (PEP) throughthe actions of pyruvate kinase (PK) and lactic dehydrogenase (LDH). Theoxidation of NADH was monitored by following the decrease of absorbanceat 340 nm (ε340=6.22 cm⁻¹ mM⁻¹) using a HP8452 spectrophotometer.Typical reaction solutions contained: 4 mN PEP; 0.15 mM NADH; 28 unitsof LDH/mL; 16 units of PK/mL; 3 mM DTT; 0.125 mM Syntide-2; 0.15 mM ATP;25 mM MgCl₂ in 50 mM TRIS, pH 7.5; and 400 mM NaCI. Assays wereinitiated with 10 nM of FL-CHK1. K_(i) values were determined bymeasuring initial enzyme activity in the presence of varyingconcentrations of test compounds. The data were analyzed using EnzymeKinetic and Kaleidagraph software.

[1018] CDK2/Cyclin A and CDK4/Cyclin D Assays

[1019] Cyclin-dependent kinase activity was measured by quantifying theenzyme-catalyzed, time-dependent incorporation of radioactive phosphatefrom [³²P]ATP into a recombinant fragment of the retinoblastoma protein.Unless noted otherwise, assays were performed in 96-well plates in atotal volume of 50 pL, in the presence of 10 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]) (pH 7.4), 10mM MgCl₂, 25 μM adenosine triphosphate (ATP), 1 mg/mL ovalbumin, 5 μg/mLleupeptin, 1 mM dithiothreitol, 10 mM β-glycerophosphate, 0.1 mM sodiumvanadate, 1 mM sodium fluoride, 2.5 mM ethylene glycol-bis(β-aminoethylether)-NN,N′N′-tetraacetic acid (EGTA), 2% (v/v) dimethylsulfoxide, and0.03-0.2 μCi [³²P]ATP. The substrate (0.3-0.5 μg) was purifiedrecombinant retinoblastoma protein fragment (Rb) (residues 386-928 ofthe native retinoblastoma protein; 62.3 kDa, containing the majority ofthe phosphorylation sites found in the native 106-kDa protein, as wellas a tag of six histidine residues for ease of purification). Reactionswere initiated with CDK2 (150 nM CDK2/Cyclin A complex) or CDK4 (50 nMCDK4/Cyclin D3 complex), incubated at 30° C., and terminated after 20minutes (min.) by the addition of ethylenediamninetetraacetic acid(EDTA) to 250 mM. The phosphorylated substrate was then captured on anitrocellulose membrane using a 96-well filtration manifold, andunincorporated radioactivity was removed by repeated washing with 0.85%phosphoric acid. Radioactivity was quantified by exposing the driednitrocellulose membranes to a phosphorimager. Apparent Ki values weremeasured by assaying enzyme activity in the presence of differentcompound concentrations and subtracting the background radioactivitymeasured in the absence of enzyme. The kinetic parameters (kcat, Km forATP) were measured for each enzyme under the usual assay conditions bydetermining the dependence of initial rates on ATP concentration. Thedata were fit to an equation for competitive inhibition usingKaleidagraph (Synergy Software), or were fit to an equation forcompetitive tight-binding inhibition using the software KineTic (BioKin,Ltd.). Measured K_(i) values for known inhibitors against CDK4 and CDK2agreed with published IC₅₀ values. The specific activity of CDK4 was thesame whether complexed to full-length cyclin D3 or the truncated CyclinD3 construct; both complexes also yielded very similar K_(i) values forselected inhibitors.

[1020] FAK Assay

[1021] FAK HTS utilized the fluorescence polarization assay provided byLJL Biosystems. The kinase reaction contained: 100 mM Hepes pH 7.5, 10mM MgCl₂, 1 mM DTT, 1 mM ATP, and lmg/ml poly Glu-Tyr (4:1). Thereaction is initiated by the addition of 5riM FAKcd409. The reaction isterminated by the addition of EDTA followed by addition offluor-labelled peptide and anti-phosphotyrosine antibody, both providedby LJL Biosystems. Inhibition results are read on a Analyst (LJL)detector.

[1022] TIE-2 Spectrophotometric Assay

[1023] The kinase-catalyzed production of ADP from ATP that accompaniesphosphoryl transfer to the random copolymer poly(Glu₄Tyr) was coupled tothe oxidation of NADH through the activities of pyruvate kinase (PK) andlactate dehydrogenase (LDH). NADH conversion to NAD⁺ was monitored bythe decrease in absorbance at 340 nm (ε=6.22 cm⁻¹ mM⁻¹) using a BeckmanDU650 spectrophotometer. Typical reaction solutions contained 1 mMphosphoenolpyruvate, 0.24 mM NADH, 40 mM MgCl₂, 5 mM DTT, 2.9 mg/mLpoly(Glu4Tyr), 0.5 mM ATP, 15 units/mL PK, 15 units/mL LDH in 100 mMHEPES, pH 7.5. Assays were initiated with the addition of 4 to 12 nMphosphorylated Tie-2 (aa 775-1122). Percent inhibition was determined intriplicate at a 1 μM level of inhibitor.

[1024] TIE-2 DELFIA Assay

[1025] Formation of phosphotyrosine was monitored using biotinylatedp34cdc2 (aa6-20=KVEKIGEGTYGVVYK) peptide as substrate. Biotinylatedpeptide was immobilized using NeutrAvidin™ coated 96-well microtiterplates followed by detection using anti-phosphotyrosine-antibody (PY20)conjugated to europium N1 chelate. Typical assay solutions contained: 1μM biotinylated p34cdc2 peptide, 150 μM ATP, 5 mM MgCl₂, 1 mM DTT, 0.01%BSA, 5% glycerol, 2% DMSO, 25 mM HEPES pH 7.5. The assay was initiatedin the NeutrAvidin plate with 50 nM of TIE2 intracellular domain. Thekinase reaction was terminated with 50 mM EDTA. Plates were then washed,and europium antibody added. After incubation, they were again washed,and DELFIA™ Enhancement Solution added. Plates were read at standardEuropium time-resolved settings (ex 340 nm, em 615 nm, delay 400 μsec,window 400 μsec). Per cent inhibition was calculated with reference tointraplate wells which had added DMSO rather than compound in DMSO, withbackground subtracted from both experimental and control with referenceto an intraplate well which had EDTA added prior to addition of enzyme.

[1026] HUVEC Proliferation Assay

[1027] This assay determines the ability of a test compound to inhibitthe growth factor-stimulated proliferation of human umbilical veinendothelial cells (“HUVEC”). HUVEC cells (passage 3-4, Clonetics, Corp.)were thawed into EGM2 culture medium (Clonetics Corp) in T75 flasks.Fresh EGM2 medium was added to the flasks 24 hours later. Four or fivedays later, cells were exposed to another culture medium (Fl 2K mediumsupplemented with 10% fetal bovine serum (FBS), 60 μg/mL endothelialcell growth supplement (ECGS), and 0.1 mg/mL heparin).Exponentially-growing HUVEC cells were used in experiments thereafter.Ten to twelve thousand HUVEC cells were plated in 96-well dishes in 100μl of rich, culture medium (described above). The cells were allowed toattach for 24 hours in this medium. The medium was then removed byaspiration and 105 μl of starvation media (Fl2K+1% FBS) was added toeach well. After 24 hours, 15 μl of test agent dissolved in 1% DMSO instarvation medium or this vehicle alone was added into each treatmentwell; the fmal DMSO concentration was 0.1%. One hour later, 30 μl ofVEGF (30 ng/mL) in starvation media was added to all wells except thosecontaining untreated controls; the final VEGF concentration was 6 ng/mL.Cellular proliferation was quantified 72 hours later by MTT dyereduction, at which time cells were exposed for 4 hours MTT (PromegaCorp.). Dye reduction was stopped by addition of a stop solution(Promega Corp.) and absorbance at 595 λ was determined on a 96-wellspectrophotometer plate reader.

[1028] IC₅₀ values were calculated by curve-fitting the response of A⁵⁹⁵to various concentrations of the test agent; typically, sevenconcentrations separated by 0.5 log were employed, with triplicate wellsat each concentration. For screening compound library plates, one or twoconcentrations (one well per concentration) were employed, and the %inhibition was calculated by the following formula:

% inhibition=(control−test)÷(control−starvation)

[1029] where

[1030] control=A⁵⁹⁵ when VEGF is present without test agent

[1031] test=A⁵⁹⁵ when VEGF is present with test agent

[1032] starvation=A⁵⁹⁵ when VEGF and test agent are both absent.

[1033] Cancer Cell Proliferation (MV522) Assay

[1034] The protocol for assessing cellular proliferation in cancer cellsis similar to that used for assessments in HUVEC cells. Two thousandlung cancer cells (line MV522, acquired from American Tissue CulturalCollection) were seeded in growth media (RPMI1640 medium supplementedwith 2 mM glutamine and 10% FBS). Cells are allowed to attach for 1 dayprior to addition of test agents and/or vehicles. Cells are treatedsimultaneously with the same test agents used in the HUVEC assay.Cellular proliferation is quantified by MTT dye reduction assay 72 hoursafter exposure to test agents. The total length of the assay is 4 daysvs. 5 for HUVEC cells because MV522 cells are not exposed to starvationmedium.

[1035] Mouse PK Assay

[1036] The pharmacokinetics (e.g., absorption and elimination) of drugsin mice were analyzed using the following experiment. Test compoundswere formulated as a solution or suspension in a 30:70 (PEG 400:acidified H₂O) vehicle or as a suspension in 0.5% CMC. This wasadministered orally (p.o.) and intraperitoneally (i.p.) at variabledoses to two distinct groups (n=4) of B6 female mice. Blood samples werecollected via an orbital bleed at time points: 0 hour (pre-dose), 0.5 h,1.0 h, 2.0 h, and 4.0 h, and 7.0 h post dose. Plasma was obtained fromeach sample by centrifugation at 2500 rpm for 5 min. Test compound wasextracted from the plasma by an organic protein precipitation method.For each time bleed 50 μL of plasma was combined with 1.0 mL ofacetonitrile, vortexed for 2 min. and then spun at 4000 rpm for 15 min.to precipitate the protein and extract out the test compound. Next, theacetonitrile supernatant (the extract containing test compound) waspoured into new test tubes and evaporated on a hot plate (25° C. ) undera steam of N₂ gas. To each tube containing the dried test compoundextract 125 μL of mobile phase (60:40, 0.025 M NH₄H₂PO₄+2.5 mL/LTEA:acetonitrile) was added. The test compound was resuspended in themobile phase by vortexing and more protein was removed by centrifugationat 4000 rpm for 5 min. Each sample was poured into an HPLC vial for testcompound analysis on an Hewlett Packard 1100 series HPLC with UVdetection. From each sample, 95 μL was injected onto aPhenomenex-Prodigy reverse phase C-18, 150×3.2 mm column and eluted witha 45-50% acetonitrile gradient run over 10 min. Test-compound plasmaconcentrations (μg/L) were determined by a comparison to standard curve(peak area vs. conc. μg/mL) using known concentrations of test compoundextracted from plasma samples in the manner described above. Along withthe standards and unknowns, three groups (n=4) of quality controls (0.25μg/mL, 1.5 μg/mL, and 7.5 μg/mL) were run to insure the consistency ofthe analysis. The standard curve had an R2>0.99 and the quality controlswere all within 10% of their expected values. The quantitated testsamples were plotted for visual display using Kalidagraph software andtheir pharmacokinetic parameters were determined using WIN NONLINsoftware. Example 1(a) provided the following results: 0.69 (Mouse pK,AUC, ip, μg-h/ml); 0.33 (Mouse pK, AUC, po, μg-h/ml).

[1037] Human Liver Microsome (HLM) Assay

[1038] Compound metabolism in human liver microsomes was measured byLC-MS analytical assay procedures as follows. First, human livermicrosomes (HLM) were thawed and diluted to 5 mg/mL with cold 100 mMpotassium phosphate (KPO4) buffer. Appropriate amounts of KPO4 buffer,NADPH-regenerating solution (containing B-NADP, glucose-6-phosphate,glucose-6-phosphate dehydrogenase, and MgCl₂), and HLM were preincubatedin 13×100 mm glass tubes at 37 C for 10 min. (3 tubes per testcompound—triplicate). Test compound (5 μM final) was added to each tubeto initiate reaction and was mixed by gentle vortexing, followed byincubation at 37° C. At t=0, 2 h, a 250-μL sample was removed from eachincubation tube to separate 12×75 mm glass tubes containing 1 mLice-cold acetonitrile with 0.05 μM reserpine. Samples were centrifugedat 4000 rpm for 20 min. to precipitate proteins and salt (BeckmanAllegra 6KR, S/N ALK98D06, #634). Supernatant was transferred to new12×75 mm glass tubes and evaporated by Speed-Vac centrifugal vacuumevaporator. Samples were reconstituted in 200 μL 0.1% formicacid/acetonitrile (90/10) and vortexed vigorously to dissolve. Thesamples were then transferred to separate polypropylene microcentrifugetubes and centrifuged at 14000×g for 10 min. (Fisher Micro 14, S/NM0017580). For each replicate (#1-3) at each timepoint (0 and 2 h), analiquot sample of each test compound was combined into a single HPLCvial insert (6 total samples) for LC-MS analysis, which is describedbelow.

[1039] The combined compound samples were injected into the LC-MSsystem, composed of a Hewlett-Packard HP1100 diode array HPLC and aMicromass Quattro II triple quadruple mass spectrometer operating inpositive electrospray SIR mode (programmed to scan specifically for themolecular ion of each test compound. Each test compound peak wasintegrated at each timepoint. For each compound, peak area at eachtimepoint (n=3) was averaged, and this mean peak area at 2 h was dividedby the average peak area at time 0 hour to obtain the percent testcompound remaining at 2 h.

[1040] The results of the testing of the compounds using various assaysare summarized in the table below, where a notation of “% @” indicatesthe percent inhibition at the stated concentration, “*” values representK_(i) (nM) or % inhibition at a compound concentration of 1 μM for * or50 nM for **, unless otherwise indicated. “NI” indicates no significantinhibition TABLE 1 HUVEC + % HUVE albumin MV522 remain FLVK FLVK- Lck-CHK- FGF- CDK2 CDK4 C IC50 IC50 IC50 (HLM, Ex # ** P** P* 1* P* * * (nM)(nM) (μM) 2 h)  2(b)  300 425   549   228 μM 2,200 8,000  2(c) 2600   50μM   26 μM  1(a)   0.3  2  88    5.2    27   19   13    54    0.35  98 3   6.6  65  37%    4.8   112   16   23    930    2.2  8(a)   3.2  23 43%   530    42  >100 μM  >100 μM >1000 >10  8(b)  72    12% @ 50 μM 2(d)   3.7  43%    91    68   53   53    450    0.18  1(c)   1.4  4.7 46%    78   560   670 >1000 >10  2(a)  40    61%   610  1600 >1000   0.58 @20 μM  1(b)   2.2   1400  4000  1300 >1000 >10  8(c)   2.6  16 34%    >10,000  >100 μM  >100 μM    280 >10  9(a)   2.4  16 162   400 1700   870 >10  9(b)  24   448  2(e)  40    5% @    20 μM 10   9   9100 >700 >10 20(a)  29  12.7    200    9.4  52 20(b)   1.6  8  23%    28%    8.2 Ca. 10 14  15    12% @25 μM  7  18  1,300 17  11   532  8(b)  1182,000  4(a)   0.65  1.4  68% NI    15.4 NI   19%     3  30    6.3  3523   1.6  2.1  12% NI    14% NI   17%     9.5  106    5.7  74 21   4.6 >700 11 12 34,000 22(b)   0.63  1.2    21.5     4.8    85 22(a)   0.22 0.2    12 >10 22(c)   0.64    38  4(b)   2.7  1.9  13%    4.9    25 205    3.2  63 @ 1 μM 12(a)   1.8  6.9  17%    19     6  87    2.1  5912(b)   0.48  1.8  32%    31     4.8  44 >10  29 18  12.5 19(b)   0.49 6.6  58% NI    60% NI   11%     2.9  27    4.3 137 19(a)  13.8  6.8 16%    92%    44 @ 1 μM 19(c)  5.9  50%    68%    17 12(c)   1.6 19(d)  0.72  33%    39%     6.8  34 >10  36  5(a)   0.03  28%    10.4    12   9.6 12(d)   0.39  31%    61%     8.1 >10  51 13   1.3  61%    74%    3.9  28 >10  69 15  15 16(a)   0.08  28% NI    65% NI NI     4.5 112    8  7*  6(a)   0.74  33%    67%     8.5  50    3.5  69*  5(b)  0.9  78%    14     3.7  33    8.5 16(b)   0.34  22%    73%     4.7 140 >10  50 16(c)  1.1    100- >10   1000 16(d)   0.43  33%    90%   11 >10 16( )   1.3  8%    59%     4.9  106 >10  40  6(b)  0.15  81%   95%     8  60    4 128 16(f)  2.8  >30 >10 19(e)  20  >300 30(a)  1.7  45%    94%     1.6  22    5.7  64 19(f)   0.18  52%    58%    2.3  16    3.9  98 46  3.5 19(g) 30(b)  2.2    90 19(q)   0.86  19%   59%    18 1920  90 30(c)   0.83  44%    82%     2.5  21  54 19(h) 5.9    600    7.9 44  9.6  >700 38(a)   0.22  77%    74%     4.5  20  10.7  72 45(b)  99%  86%    79%     1.9  11.5    4.4  97 45(a)   0.062    3.1 ca. 15    3.5  97 19(l)  4.7  >300 42(a)   0.046  79%  53    65    0.8   8    5.5  92 38(b)  72%    79 19(j)   0.33  23%    44%     2.2 50 >10  66 42(b)   0.35  75%    27%     2.1  29    2.1  81 19(k)  100% 37%    41%     2.6  28    4  58 33(b)   0.66  76%  63%    77%     0.8 11.5   15  45 26  1.1    6.6    3.2 19(l)   0.72  36%    88%     6.8 100    3.8 19(m)   0.68  35%    23%  94 >10  61 33(a)   3.8  42%  9%   0    56    2%    7%     0.5   2.7 >10  29 19(n)   0.54  26%    48%    3.4  23    2.9 33(c)   0.28  26%    76%   6.6 >10  16 33(d)   0.14 55%    24 >300    8  22 40(a)  17.9 41(aa)   0.11  49%    37%     1  5.2 >10 100 41(b)   0.26  24%    31%     2   9.8 >10  80 (UV) 42(e)  1.1  95 42(d)   1.7  44 >10 43   2.6  56%  24  2 19(o)  89%  20 41(c)  0.22  83%  36%    77%     0.4   5.3  68 41(d)   0.093     0.9  6.441(a)   0.03  94%  50%    0    20    0    6%     0.48   4.4 >10  9619(p)   1.5 41(e)   0.22  21%    31%     0.15   5.6,  22   6.1 41(f)  0.11  84%  65%    92%     0.45  20  59 41(g)   0.1  36%    95%    0.9 >10  52 30(d)   0.37   3.8 30(e)   0.37  62%    92%  29 33(e)  1.7  70%  2%    68%     0.46   5 >10  54 33(f)   8  17  31 41(h)   90% 30%     2  25  8 47   0.25  50%    88% 31(a)   0.29  77%*    95%    0.7  10  58 41(l)   0.04  38%*    76%     0.25   3.3  48 35(u)  79%  2.8  27 32(a)   <0.1  86%*    96%     0.16   4.5  2 41(k)   2.95  20%   49%  48 41(l)   0.24  63%*    66%  386 41(m)   0.75  40%    67%  23 0 41(n)   0.2  66%*    87%  28  70 31(b)   <0.1  66%    97%     5.6  241(o)   0.05  77%    74%  10  94 31(c)   <0.1  81%    98%  11.4  8735(gg)  23% >100 33(g)  15% 34  97%  78%    95%  15  28 50 35(v)  72% 11%    59%  22  26 35(w)  59%  35 35(x)  75%   2  37 35(a)  76%  12%   59%   2.1  33 35(b)  49%  12%    59%  35 35(c)  76%  11%    42%   6.3 17 41(p)   0.06  49%    0    90    6%    3%     0.27   2.6 >10  6242(c)  95%   1 to 3 41(dd)  98%  50%    69%   5.8  7 41(bb)  99%  76%   88%   1 to 3 110 35(y)  99%  29%    82%   1 to 3  7 35(d)  76% >10031(d)  96%  52%    0    14    5%    9%    1.3 ca. 13    5.2 110 41(q) 100%  53%    91%   2.7 35(e)  99%  56%    69%   4.8 >10  34 35(f)  100%  8  15 35(g)  100% ca. 15  53 35(h)  100%   3.6  9 35(i)  100%   4.735(j)  99%   1.5  5 35(k)  85%  6%    0    34%    8%    7%   2.2 >10  1441(ee)   0.13  13%    0    94%    0    2%    0.24   4.3,    9.4  47 2.735(z)  95%   7.1  2 35(aa)  99%   5  15 41(r)  100  55%    0    92%    0   5%  11  83 41(cc)  97%  41%   95% >100 35(l)  90%  12 35(cc)  89% 15%    0    74%    5%    6%    0.05   1.6  31 35(ee)  82%   3  1335(ff)   0.11  25%    75%   5.8  31 35(dd)   0.6  17%    0    75    7%   8%    0.18   2.9 >10  26 35(bb)  87%   4.1  8 32(b)   0.08  70%   95%  21 >10 35(hh)  100%  34%    73%   7 35(m)   0.04  61%    82%  3548(a)   0.37  13%    0    14    0    0   8.8  55 39(a)  53%    1.4 ca.50  70 35(n)   0.83  58%    23%    92    4%   10%    0.11  11    5.1  4741(s)   0.23  53%    86% 35(o)  39%  17%    44% >100 41(t)   0.06  51%   0    85%    1%    2%   3.8  87 32(c)   0.27  52%    96%   >30 36(b) 85%  22%    43%   >30 37(d)  26%  10%    38% >100 37(c)  83%  12%   39%  12  21 37(b)  48%  8%    36%  30-  100 59(a) 41(u)   0.08  54%   74%   7.9 41(hh)  98%  13%    74%   3.9  72 36(c)  89%  28%    60%  >30 36(a)  87%  19%    38%  19  58 35(p)  62%  5%    11%   >30 35(q) 92%  42%    51%  18 40(b)  89%  32%    92% 41(ff)  98%  15%    12   5.6 68 37(a)  57%  6%    35%  15  21 41(v)  68%*  52%    68%  12 41(ii) 57%  18%    11  13  85 35(r)   0.11  16%    20    0.36   2.3 >10  5135(s)  60%*  18%    64%   4.6  16 35(t)  59%*  12%    63%   4  7 41(ll) 95%  14%    91%  23 41(w)  97%  49%    67% ca. 10 41(x)  98%  66%   3.4   4.6 100 41(mm)  93%  6%    46%    1.3  14.4  94 41(jj)  87% 19%    81%  21 41(y)  98%  61%    86%  30- 100 31(e)   0.02  43%    62%  6.2    8.6  49 40(c)  24%  28%    59% 41(gg)  84%  27%    3.5   9.5 50 41(nn)  57%  7%    91% >100 41(j)  98%  16%    41%   7.7 48(b)  97% 6%    77% ca. 8 41(z)  100%  54%    74%   7.5 41(kk)  100%  26%    97% 16  63 39(b)   2.8  10%    50%   >10 31(f)  97%  62%    99%   >10 59(b)49(a)   0.04  11%    79 ca. 4    8.4 59(c) 49(b)  98%  9%    80% ca. 1056   5% 35(ii)  44% 59(d) 57  100%  30%    89% 59(e) 58  98%  19%    98%

[1041] TABLE 2 HCT-116 IC50 Ex # CDK2* CDK4* CHK1* FLVK-P* Lck* FGF*(μM) 24(a)  0.017  0.0051  0.028  0.0983 67% 72% 0.23 24(b)  0.021 0.0032  0.02  0.0331 96% 88% 0.37 24(c)  0.0034  0.0015  0.044  0.014293% 89% 0.44 24 17% 16% NI @ (m) 20 μM 24(l)  0.086  0.071 62% @ 3.8 20p.M 24(d)  0.083  0.017  0.056  0.125 51% 66% 0.023 24(e)  0.03  0.004475% 52% 0.15 24(f)  0.0072  0.0074 97% 89% 1.5 24(g)  0.13  0.029  1.67 0.194 >5 24(o)  0.029  0.2 2.2 24(h)  0.054  0.053 3.6 24(l)  0.055 0.013 1.7 24(j)  2.1  0.32 24(k)  0.056  0.0072 81% 89%  0.16 0.2 25(a) 0.08  0.021 49% 44% 62% 0.051 24(n)  0.035  0.019 1.5 25(b)  0.112 0.048 83% 87% 87% 2.1 25(c)  0.233  0.0155 90% 96% 0.25 25(d)  0.16 0.098 87% 60% 80% 25(e)  0.477  0.181 16% 13% 26% 25(f)  0.39  1 NI 58%56% 0.098 25(g)  0.08  0.021 21% 76% 82% 2 25(h)  0.17  0.024 86% 87 910.32 25(l)  0.021  0.02 >5 24(p)  0.089  0.092 0.44 25(j)  0.079  0.01670 0.0083

[1042] TABLE 3 Example # CHK-1* CDK1* CDK2* CDK4* FLVK* 28(d) 0.018 93%66% 87% 27(j) 15% @ 50 uM 27(a) 0.198 NI @ 1 NI @ 100 28% @ 5 71% μM μMμM 27(b) 28% @ 50 μM 28(a) 0.108 77% 75% 79% 84% 27(c) 11% @ 5 μM 28(b)0.0143 97% 98% 96% 27(d) 14% @ 10 μM 27(e) 0.757 34% 27(l) 0.227 85% 73%92% 27(f) 0.35 0.223 3.3 0.78 49% 27(h) 0.311 84% 27(k) 24 28(c) 1.1434% 27(g) 0.85 52(b) 0.08 0.041 0.241 0.117 94% 55 10 52(a) 0.263 39%60% 53(a) 0.301 24 13% @ 5 28% @ 5 μM μM 29(b) 0.138 0.9 3 3.9 29(a) NI@ 25 μM 29(c) 0.174 56% 2.2 2 29(d) 10 29(e) 0.074 0.593 1.4 2 33% 29(f)0.418 51 0.087 0.146 84% 79% 29(r) 0.072 0.066 1.3 1.1 29(g) 0.068 0.391.4 1.1 29(h) 0.14 1.3 3 2.2 54(d) 0.68 NI @ 1 μM 54(b) 3.1 29(l) 0.10426% 3.1 5 53(d) NI @ 100 μM 54(e) 0.342 NI @ 1 μM 54(a) 0.896  1% 53(c)1.1 29(j) 0.533 31% 29(q) 11 11% 29(p) 0.232  6% 53(b) 1.4 29(k) 1.354(f) 2.9 54(c) 0.125 NI 54(g) 0.195  3% 29(o) 46 53(e) 0.886 13% 29(l)1.4  7% 29(n) 16 29(m) 1 54% 53(f) 7.3 54(h) 1 29(s) 11 54(j) 0.42454(i) 0.461 29(t) 0.072 29(u) 0.151 53(g) 1.5 54(l) 0.99 54(k)

Library Example I

[1043]

[1044] The three library building blocks (“amine templates”)6-(3-aminophenoxy)-3-E-styryl-1H-indazole (Y═O),6-(3-aminobenzoyl)-3-E-styryl-1H-indazole (Y═CO), and6-(3-aminophenyl)amino-3-E-styryl-H-indazole (Y═NH) were prepared asdescribed in Example 7, Example 18, and Example 46 respectively. 0.1 Msolutions of the acid, the amine template,o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluorophosphate and triethylamine were prepared separately inanhydrous DMF. To each tube in an array of 8×11 culture tubes (10×75 mm)was added 105 μL (0.0105 mmol) of a different acid. To this was added100 μL (0.01 mmol) of the amine solution, 105 μL (0.0105 mmol) of thetriethylamine solution followed by 105 μL (0.0105 mmol) of theo-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluorophosphate solution. The reactions were stirred in a heatingblock at 50° C. for 3 h. The reaction mixtures were transferred to a 1mL 96-well plate using a liquid handler. The solvents were removed usingthe SpeedVac™ apparatus and the crude reaction mixtures were redissolvedin DMSO to give a final theoretical concentration of 10 mM.

[1045] The compounds in the table were tested for inhibition of theproliferation of HUVEC at a nominal concentration of 10 nM, and theresults are listed in Table I below, calculated from:

% inhibition=(control-treated)/(control-starvation)×100

[1046] Under these testing conditions, >50% inhibition is consideredsignificant. TABLE I LIBRARY Y = Y = R⁸ CO Y = O NH

134 127 135

124 145 118

128 94 115

134 138 112

3 56 111

30 91 109

101 157 105

−62 5 105

108 115 104

124 147 103

125 124 103

158 131 101

142 101 98

137 137 95

131 68 94

58 68 94

75 78 87

113 150 86

72 87 85

128 92 81

113 30 80

51 35 79

125 122 78

87 80 77

26 52 76

99 52 75

54 85 71

80 91 64

71 52 60

21 76 43

81 93 40

87 86 34

25 70 32

2 52 30

24 96 30

35 64 30

37 48 30

57 70 29

52 42 27

47 69 25

51 71 25

35 57 24

18 51 23

45 57 23

19 22 20

32 32 20

10 24 20

24 45 19

−13 18 17

−36 −6 17

−2 25 17

3 24 16

5 25 16

−1 30 15

33 42 13

3 36 13

14 90 12

−37 25 11

81 64 11

47 17 10

27 30 10

5 23 7

21 40 7

50 112 6

96 134 6

42 13 6

−20 25 6

44 82 5

33 32 3

0 4 2

20 43 0

8 23 0

28 80 −1

10 19 −2

12 40 −3

3 46 −3

39 −4

37 20 −5

−11 52 −7

10 59 −7

27 48 −8

64 83 −8

35 42 −9

27 52 −9

31 20 −17

56 17 −17

−20 18 −18

64 38 −20

Library Example II

[1047] (a) When Y═S in Formula I

[1048]6-[2-(Pentafluorophenoxycarbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H--indazole(Y═S) was prepared as decribed in Example 35(a). Solutions of 261 amines(1.5 μmol), and Et₃N (0.1393 pL, 1.0 μmol), dissolved in DMF (15 μL),were distributed in to the wells of a 96-well plate. In cases where theamine was used as a hydrochloride salt, additional Et₃N (0.4179 iL, 3.0μmol) was added to liberate the free base. Each of the wells was treatedwith a solution of pentafluorophenyl ester (0.5395 mg, 1.0 μmol)dissolved in DMF (30 μL), then agitated for 24 h at room temperature.The crude reaction mixtures were concentrated using a GeneVac™apparatus, and then diluted with DMSO to a final concentration of 10 mM.

[1049] (b) When Y═NH in Formula I

[1050] Solutions of 263 amines (2.0 μmol), and Et₃N (0.4181 μL, 3.0μmol) were dissolved in DMF (20 μL) and distributed into the wells of a96-well plate. In cases where the amine was used as a hydrochloridesalt, additional Et₃N (0.5575 μL, 4.0 μmol) was added to liberate thefree base. Each of the wells were treated with a solution of:6-[2-carboxyphenyl-amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole(0.447 mg, 0.75 μmol) dissolved in DMF (20 μL), followed by a solutionof HATU (0.570 mg, 1.5 μmol) dissolved in DMF (10 μL), and then agitatedfor 72 h at room temperature. The crude reaction mixtures wereconcentrated using a GeneVac™ apparatus, and then diluted with DMSO to afinal concentration of 10 mM.

[1051] The compounds in the Library Table II were tested for inhibitionof the proliferation of HUVEC at a nominal concentration of 0.5 and 2 nMfor Y═S, and the results are listed in below, as calculated from:

% inhibition=(control-treated)/(control-starvation)×100

[1052] Under these testing conditions, >50% inhibition is consideredsignificant. TABLE II LIBRARY R¹ 0.5 nM 2 nM

19 89

38 2

37 16

39 15

35 10

32 31

5 14

14 55

23 44

25 35

30 23

5 19

70 105

25 15

44 19

38 5

23 6

4 20

21 60

34 61

23 23

26 37

2 6

32 24

32 6

48 8

45 88

17 4

8 21

15 27

22 24

22 23

16 20

10 24

28 22

37 12

49 91

40 31

18 32

6 43

30 78

34 58

22 20

19 28

6 1

20 10

31 3

32 10

31 −1

6 4

4 29

23 61

18 24

21 15

−1 26

−6 0

18 5

23 17

20 2

37 15

0 4

5 1

8 18

3 15

23 16

42 22

−9 1

25 −5

16 7

27 2

49 −9

18 40

5 9

8 23

16 21

13 23

8 22

2 −19

17 1

7 −1

5 −6

26 −19

23 −32

2 −3

18 25

1 13

4 4

18 22 H-X1 9 30

7 25

16 17

13 31

95 106

59 97

30 86

22 43

33 64

28 29

31 20

42 80

25 53

65 110

29 58

52 107

31 36

4 10

8 23

13 20

33 18

20 25

62 99

6 16

17 13

19 22

39 18

44 5

43 96

19 55

29 92

49 109

25 14

24 84

19 24

47 107

35 40

26 31

53 75

8 21

70 112

72 109

26 31

28 14

−6 41

12 76

33 94

27 17

44 28

55 50

21 90

12 53

21 64

35 63

21 −5

1 65

28 103

51 105

44 97

44 40

47 −4

47 89

12 29

44 100

35 69

16 2

32 92

92 103

9 1

56 96

26 2

39 13

19 5

24 31

35 106

15 36

69 59

−11 42

16 42

15 95

20 92

19 −1

31 30

−1 14

9 34

6 44

1 52

18 −2

9 −9

40 94

38 68

25 40

34 99

30 94

24 99

19 101

20 92

15 99

16 37

17 23

70 111

60 99

75 114

81 95

24 86

−3 64

26 71

14 60

51 108

8 37

15 23

20 32

35 63

28 47

26 16

18 11

13 7

28 69

18 43

11 47

19 86

26 83

50 111

45 103

53 95

31 108

69 104

36 106

58 100

63 104

12 55

16 73

18 −3

16 17

32 35

36 66

68 49

26 39

15 4

25 31

65 90

21 39

10 29

16 2

22 36

18 29

25 25

27 80

30 70

10 23

50 40

51 67

23 51

31 66

86 107

46 103

26 59

30 61

41 16

15 8

74 101

78 60

58 37

34 90

34 69

19 35

15 −1

11 15

15 −9

12

8

38

48

Library Example III

[1053]

[1054] 0.1 M solutions of the amines, triethylamine and4-dimethylaminopyridine were prepared separately in anhydrous DMF andtransferred to a glovebox. 0.1 M solution of6-[2-(carboxy)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole,Example 33(g), tetrabutylammonium salt ando-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluorophosphate was prepared in the glovebox. To each tube in anarray of 8×11 culture tubes (10×75 mm) in the golvebox was added 100 μL(0.01 mmol) of the different amine solutions followed by the addition of100 μL (0.01 mmol)tetrabutylammonium2-{3-[(E)-2-(2-pyridinyl)ethylyl]-1H-indazol-6-yl}sulfanyl)benzoatesolution, 100 μL (0.01 mmol) of the triethylamine solution, 100 μL (0.01mmol) of the 4-dimethylaminopyridine solution and 100 μL (0.01 mmol) ofthe o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluorophosphate solution. The reactions were stirred in a heatingblock at 50° C. for 1 h. The reaction mixtures were transferred to a 1mL 96-well plate using a liquid handler. The solvents were removed usingthe SpeedVac™ apparatus and the crude reaction mixtures were redissolvedin DMSO to give a final theoretical concentration of 10 mM.

[1055] The compounds in the table were tested for inhibition of theproliferation of HUVEC at a nominal concentration of 0.5 nM, and theresults are listed in Table III below, as calculated from:

% inhibition=(control-treated)/(control-starvation)×100

[1056] Under these testing conditions, >30% inhibition is consideredsignificant. TABLE III LIBRARY R % inhibition

−1

−17

4

17

6

22

−19

9

2

5

15

−22

−19

−9

−11

−17

−6

−11

−1

12

9

7

−32

−22

−15

−22

−4

4

−29

−6

−8

8

1

−38

−36

−11

−14

−20

−5

−43

−5

0

6

0

−28

−13

−21

−15

0

−18

−15

−1

−11

3

1

−27

−47

33

17

20

−29

−17

−7

0

−1

4

−43

−42

22

13

81

−23

−31

−3

0

3

13

0

−113

2

4

20

2

−3

−9

−9

−1

4

12

9

−6

−2

5

6

18

20

−23

−12

22

9

7

−4

4

7

7

18

11

−31

−22

−5

−1

−7

−22

−3

11

4

20

15

−45

−37

−20

−4

0

−29

−26

3

8

12

6

−57

−25

−41

−21

−28

−20

−20

3

11

1

−5

−60

−46

−22

−20

−7

−28

−10

−13

13

−7

−13

−45

−40

−2

−11

−31

−30

−11

−2

18

7

1

0

0

24

14

61

9

1

1

4

1

8

−15

−12

52

19

13

−7

−26

7

9

18

10

−37

−2

43

5

1

−3

−13

−1

−1

16

4

−23

−20

−15

10

−18

−9

29

1

10

0

9

−3

−11

22

9

−5

−19

−6

−12

−1

−7

2

−34

−13

13

48

36

−8

−11

1

−4

10

−1

−33

−19

−6

2

−21

−16

−25

−9

1

4

37

−12

−20

−22

7

−22

−12

0

−6

13

−1

−11

11

15

−8

1

3

9

2

8

15

14

3

−31

−2

11

13

10

3

6

2

−1

3

18

−17

−8

3

0

18

7

−6

2

3

14

10

−20

−10

4

10

9

−7

−3

4

8

10

7

−9

46

2

23

11

−10

−4

7

9

10

15

−18

−3

−2

5

−13

−9

−2

−6

17

19

18

−24

0

−6

3

−20

−16

−19

1

3

6

18

−18

−9

2

14

−10

−7

4

11

11

8

23

1

−20

0

57

24

1

−10

−8

−2

5

3

[1057] TABLE 4

R CHK-1 @ 20 μM

30.6

28.3

22.5

21.7

40

27.8

20.2

57.7

35.5

24.2

31.1

13.7

23.9

48.6

19.5

32.3

24.9

25.8

94.9

38.7

72

21.1

31.4

28.3

28.5

28.1

25.7

23.9

36.3

45.4

32.7

24.7

52.7

38.6

23.6

39.8

28.1

33

52.4

38.6

32.3

42.9

24.1

31.6

[1058] TABLE 5 % Inhibition @ 1 μM Example # Tie2-P FAK 41(a) 50   5 41(ee) 41   7  41(p) 49   9  41(r) 56   5  41(t) 51   9  48(a) 52  11 31(d) 46   6  33(a) 35  12  35(k) 55   7  35(dd) 48   4  35(n) 82   1 35(cc) 47   7   1(a) 95* 69*  3     NI* 26*  8(a) 55*  3*  2(d) 90* NI* 8(c) 31* 15*  9(b) 88* NI* 10     20* NI* 17     50   4(a) 69  11    40   4(b) 29   2(c) NI  22(a)  8  23      5  22(b) NI  21     27  12(a)NI  19(a) 18  19(c) NI  12(c) 17  19(d) 15   5(a) 44  16(a) 10  16(b)52  24(a) 91* 24(b) 92* 24(c) 94  30(a) 19   8(d) 10 

[1059] Determination of Inhibitor Concentration in Mouse Plasma afterIntraperitoneal and Oral Dosing

[1060] The dosing solution consisted of the inhibitor dissolved in oneof the following vehicles: either 30% or 60% aqueous polypropyleneglycol solution with a molar equivalent of HCl in water, or 0.5%carboxymethylcellulose in water. The final concentration was normally 5mg/ml with a dosing volume of 5 or 10 ml/kg. Taconic (Germantown, NY)female mice were dosed as a function of compound mass per body mass,usually 50 or 25 mg/kg. Blood collection was via ocular bleed at 0.5, 1,4 hr with the final time point, 7 hour, via intracardiac puncture. Theblood was centrifuged to collect plasma, which was then stored at −80°C. until analysis. Samples were prepared for analysis using an internalstandard and sodium hydroxide. After vortexing, ethyl acetate was addedand mixed for 15-20 minutes at ambient temperature. Followingcentrifugation, the resulting organic layer was evaporated andsubsequently reconstituted in acetonitrile and buffer. The samples werethen analyzed via HPLC or LC-MS.

[1061] Compound levels were quantitated by generating a standard curveof known compound concentration in mouse plasma. Compound levels wereplotted as a function of time and analyzed to provide area under theconcentration curve (AUC ng*hr/ml), maximum concentration (Cmax ng/ml),minimum concentration (Cmin or 7 hour trough ng/ml), and terminalhalf-life (TI/2 hr). The results are shown in Table 6. TABLE 6 Cmin (7Vehicle Example Dose AUC_(last) Cmax hr conc.) T_(1/2 β) PEG400:H2O #Route mg/kg (ng*hr/ml) (ng/ml) (ng/ml) (hr) pH 2.3  1 (a) IP 50 691 2832.4 30:70 19 (b) PO 50 NA 30 ∞ 60:40 19 (j) IP 25 23205 5764 456 1.660:40 19 (j) PO 50 5889 1937 63 1.2 60:40 19 (k) IP 25 428 149 15 2.260:40 19 (k) PO 50 19 8 4 2.2 60:40 31 (a) IP 25 47538 13018 1906 2.430:70 31 (a) PO 50 40863 14499 834 1.6 30:70 31 (b) IP 25 >7037 >2000177 1.7 30:70 31 (b) PO 50 2071 1100 15 1.0 30:70 31 (d) IP 25 23778464184 15073 5.3 30:70 31 (d) PO 10 49120 9740 2022 3.1 30:70 31 (d) PO25 203860 50810 3801 1.9 30:70 31 (d) PO 50 430683 76915 42478 39.330:70 31 (e) PO 25 >30339 >5000 2952 13.1 30:70 31 (f) PO25 >244545 >50000 9521 2.6 30:70 32 (a) IP 25 >20554 >4000 1273 3.730:70 32 (a) PO 50 4190 1746 40 1.1 30:70 32 (b) PO 25 490 179 18 2.130:70 32 (c) PO 25 388 161 10 2.4 30:70 33 (a) IP 25 13813 13794 54 1.130:70 33 (a) PO 100 3556 90 0.5% CMC 33 (a) PO 25 721 66 0.5% CMC 33 (a)PO 50 19067 23562 25 0.8 30:70 33 (b) IP 25 11245 1990 902 3.0 60:40 33(b) PO 50 3925 1496 76 3.0 60:40 33 (c) IP 25 697 505 7 1.2 30:70 33 (c)PO 50 183 94 5 3.0 30:70 33 (d) IP 25 5080 1738 113 1.6 60:40 33 (d) PO50 4744 1614 8 0.9 60:40 33 (e) IP 25 14323 9938 94 1.0 30:70 33 (e) PO50 13290 9967 12 0.7 30:70 33 (f) IP 25 1887 1699 6 2.4 30:70 33 (f) PO50 1436 1186 3 0.7 30:70 35 (a) IP 25 2032 2138 24 1.4 30:70 35 (a) PO50 2445 1780 10 0.9 30:70 35 (aa) PO 25 4036 4168 106 2.1 30:70 35 (b)IP 25 2840 1509 12 0.8 30:70 35 (b) PO 50 4048 5595 13 0.8 30:70 35 (c)IP 25 9408 1976 465 3.2 30:70 35 (c) PO 50 4744 909 321 4.9 30:70 35(cc) IP 25 2223 3183 6 1.4 30:70 35 (cc) PO 50 1718 1439 5 0.9 30:70 35(dd) IP 25 >23046 >4000 1364 4.1 30:70 35 (dd) PO 25 1360 444 58 2.00.5% CMC 35 (dd) PO 25 >6521 >4000 114 1.4 30:70 35 (e) IP 25 2409 127265 1.8 30:70 35 (e) PO 50 1503 1043 6 0.9 30:70 35 (ee) IP 25 546 579 21.5 30:70 35 (ee) PO 25 157 77 9 14.6 30:70 35 (f) IP 25 397 131 25 3.830:70 35 (f) PO 50 358 93 27 3.6 30:70 35 (ff) IP 25 >6301 >4000 72 1.730:70 35 (ff) PO 25 Blq Blq blq blq 30:70 35 (g) PO 25 231 61 28 16.130:70 35 (h) IP 25 59 46 1 1.5 30:70 35 (h) PO 50 26 7 2 * 30:70 35 (hh)PO 25 292 221 5 1.7 30:70 35 (i) PO 25 30:70 35 (j) IP 25 9531 8606 521.3 30:70 35 (j) PO 50 1328 2176 5 4.5 30:70 35 (k) IP 25 2640 2189 351.4 30:70 35 (k) PO 50 5529 4524 33 1.4 30:70 35 (m) IP 25 226 58 17 4.030:70 35 (m) PO 25 10 7 0 * 30:70 35 (n) PO 25 4818 3545 55 1.4 30:70 35(o) PO 25 683 486 3 1.0 30:70 35 (p) PO 25 1435 1958 5 1.3 30:70 35 (r)PO 25 4261 2601 67 1.3 30:70 35 (s) PO 25 7425 3371 86 2.2 30:70 35 (t)PO 25 3199 2801 41 1.1 30:70 35 (u) PO 25 30:70 35 (v) IP 25 4865 221516 0.9 30:70 35 (v) PO 50 >2946 >2000 26 1.0 30:70 35 (x) IP 25 951 78148 3.2 30:70 35 (x) PO 50 3516 2313 16 0.9 30:70 35 (y) IP 25 159 135 21.2 30:70 35 (y) PO 50 58 45 1 1.2 30:70 35 (z) IP 25 837 556 22 1.830:70 35 (z) PO 50 1001 806 14 1.6 30:70 36 (a) PO 25 605 445 17 1.530:70 37 (a) PO 25 30:70 37 (c) PO 25 2419 2338 9 1.2 30:70 39 (a) PO25 >14848 >4000 219 1.4 30:70 39 (b) PO 25 >30972 >5000 3148 11.8 30:70 4 (a) PO 50 NA 50 NA 60:40 41 (a) IP 25 92823 32202 3856 2.9 30:70 41(a) PO 50 48998 18433 2462 3.4 30:70 41 (aa) IP 25 6659 2427 124 2.160:40 41 (aa) PO 50 289 259 5 0.9 60:40 41 (b) IP 25 >5868 >1000 412 4.760:40 41 (b) PO 50 759 532 6 1.1 60:40 41 (bb) PO 50 2178 596 75 2.030:70 41 (c) IP 25 3397 2068 57 1.7 60:40 41 (c) PO 50 3182 1296 104 2.660:40 41 (d) IP 25 10324 2787 573 2.8 60:40 41 (d) PO 50 7072 2954 1501.5 60:40 41 (dd) PO 25 654 542 1 0.8 30:70 41 (e) IP 25 4900 1154 3011.6 60:40 41 (e) PO 50 302 113 7 1.6 60:40 41 (ee) IP 25 >28434 >50001670 4.0 30:70 41 (ee) PO 50 >25294 >5000 1214 3.4 30:70 41 (ff) PO 259176 2784 410 2.0 30:70 41 (g) IP 25 1925 1583 0 0.3 60:40 41 (g) PO 50508 842 1 0.7 60:40 41 (gg) PO 25 2692 2079 29 1.1 30:70 41 (h) IP 2526911 16005 300 1.2 30:70 41 (h) PO 50 4677 4080 7 0.7 30:70 41 (hh) PO25 5601 1526 405 7.9 30:70 41 (l) IP 25 1854 623 102 3.1 30:70 41 (l) PO50 212 104 0 0.5 30:70 41 (ii) PO 25 7094 1826 346 2.3 30:70 41 (j) PO25 1476 1008 17 1.3 30:70 41 (kk) PO 25 11612 3709 415 2.0 30:70 41 (m)IP 25 1864 501 54 2.3 30:70 41 (m) PO 50 9 5 0 blq 30:70 41 (mm) PO 252261 852 127 2.5 30:70 41 (n) IP 25 9408 1976 465 3.2 30:70 41 (n) PO 509066 2245 253 1.9 30:70 41 (o) IP 25 >33750 >5000 >5000 * 30:70 41 (o)PO 50 14717 4776 427 1.7 30:70 41 (p) IP 25 4150 866 380 5.5 30:70 41(q) IP 25 >27000 >4000 >4000 * 30:70 41 (q) PO 25 8572 1901 457 5.230:70 41 (r) IP 25 >23752 >5000 >5000 * 30:70 41 (r) PO50 >17789 >5000 >5000 * 30:70 41 (t) PO 25 >22498 >4000 1350 4.0 30:7041 (u) PO 25 875 224 51 5.6 30:70 41 (v) PO 25 10949 2338 749 4.4 30:7041 (x) PO 25 24174 4587 1268 4.2 30:70 41 (y) PO 25 Blq Blq blq blq30:70 42 (a) IP 25 19899 4027 1639 5.0 60:40 42 (a) PO 50 8384 3264 3412.0 60:40 42 (b) IP 25 3207 953 211 3.0 60:40 42 (b) PO 50 4747 2589 463.0 60:40 42 (d) IP 25 1774 886 31 1.4 60:40 42 (d) PO 50 46 28 18 BLQ60:40 45 (b) IP 25 11361 2636 1123 2.0 60:40 45 (b) PO 50 1636 427 1023.0 60:40 47 IP 25 236 39 29 19.9 30:70 47 PO 50 327 84 25 3.4 30:70 59(a) PO 25 50780 15878 1205 1.6 0.5% CMC 48 (a) IP 25 27000 4000 4000 *30:70 48 (a) PO 25 26636 4000 3857 * 30:70 48 (b) PO 25 2191 476 136 430:70 49 (a) PO 25 712 342 15 30:70 49 (b) PO 25 33750 5000 5000 30:70 5 (b) PO 10 61 12 3.1 60:40 59 (a) PO 8 7707 2489 122 1.5 0.5% CMC 59(a) PO 40 57240 13798 1879 2.4 0.5% CMC 59 (a) PO 200 156153 29975 121179.4 0.5% CMC 59 (b) PO 50 276467 50000 26880 CMC 59 (c) PO 25 32713550000 43090 CMC 59 (d) PO 8 >24696 >5000 1902 0.5% CMC 59 (d) PO40 >32297 >5000 4135 0.5% CMC 59 (d) PO 200 >12306 >20000 12743 0.5% CMC59 (e) PO 25 12510 28834 2135 21 0.5% CMC

[1062] In Vivo Assay of Retinal Vascular Development in Neonatal Rats

[1063] The development of the retinal vascular in rats occurs frompostnatal day 1 to postnatal day 14 (P1-P14). This process is dependenton the activity of VEGF (J. Stone, et al, J. Neurosci., 15, 4738(1995)). Previous work has demonstrated that VEGF also acts as asurvival factor for the vessels of the retina during early vasculardevelopment (Alon, et. al, Nat. Med., 1, 1024 (1995)). To assess theability of specific compounds to inhibit the activity of VEGF in vivo,compounds were formulated in an appropriate vehicle, usually 50%polyethylene glycol, average molecular weight 400 daltons, and 50%solution of 300 mM sucrose in deionized water. Typically, twomicroliters (2 μl) of the drug solution was injected into themidvitreous of the eye of rat pups on postnatal day 8 or 9. Six daysafter the intravitreal injection, the animals were sacrificed and theretinas dissected free from the remaining ocular tissue. The isolatedretinas were then subjected to a histochemical staining protocol thatstains endothelial cells specifically (Lutty and McLeod, Arch.Ophthalmol., 110, 267 (1992 )), revealing the extent of vascularizationwithin the tissue sample. The individual retinas are then flat-mountonto glass slides and examined to determine the extent ofvascularization. Effective compounds inhibit the further development ofthe retinal vasculature and induce a regression of all but the largestvessels within the retina. The amount of vessel regression was used toassess the relative potency of the compounds after in vivoadministration. Vessel regression is graded on subjective scale of oneto three pluses, with one plus being detectable regression judged to beapproximately 25 percent or less, two pluses being judged to beapproximately 25-75% regression and three pluses give to retinas withnear total regression (approximately 75% or greater).

[1064] For more quantitative analysis of regression, images ofADPase-stained, flat-mounted retinas were captured with a digital cameraattached to a dissecting microscope. Retinal images were then importedinto an image analysis software (Image Pro Plus 4.0, Media Cybernetics,Silver Spring, Md.). The software was employed to determine thepercentage of the area of the retina that contained stained vessels.This value for the experimental eye was compared to that measured forthe vehicle injected, contralateral eye from the same animal. Thereduction in the vascular area seen in the eye that received compound ascompared to the vehicle-injected eye was then expressed as the “percentregression” for that sample. Percent regression values were averaged forgroups of 5-8 animals.

[1065] In samples in which observation through the microscope indicatednear total regression, a percent regression value of 65-70% wasroutinely measured. This was due to stain deposits within folds ofretina, folds that were induced by the vehicle used for drug injection.The image analysis software interpreted these stain-containing folds asvessels. No attempt was made to correct for these folds since theyvaried from eye to eye. Thus, it should be noted that the percentregression values reported result from a conservative measurement thataccurately rank orders compounds, but underestimates their absolutepotency.

[1066] In Vivo Assav of Retinal Vascular Development in Neonatal RatModel of Retinopathy of Prematurity

[1067] A second model of VEGF dependent retinal neovascularization wasemployed to evaluate the activities of this series of compounds. In thismodel (Penn et. al, Invest. Ophthalmol. Vis. Sci., 36, 2063, (1995)),rats pups (n=16) with their mother are placed in a computer controlledchamber that regulates the concentration of oxygen. The animals areexposed for 24 hours to a concentration of 50% oxygen followed by 24hours at a concentration of 10% oxygen. This alternating cycle ofhyperoxia followed by hypoxia is repeated 7 times after which theanimals are removed to room air (P14). Compounds are administered viaintravitreal injection upon removal to room air and the animals aresacrificed 6 days later (P20). The isolated retinas are then isolated,stained mounted and analyzed as detail above in the development model.The effectiveness was also graded as is described for the developmentmodel. TABLE 7 Example Initial Concen. Vehicle # Model Evaluation %Inhibition (mg/ml) PEG/water 16(e) ROP ++ 36% 5 70:30 16(e) ROP +++ 54%10 70:30 16(e) ROP ++ 37% 5 70:30 16(e) ROP +/− 16% 1 70:30 19(b) ROP ++10 70:30 19(f) P8 +/++ 5 50:50 19(j) ROP +/− 10 70:30 19(j) ROP −− 170:30 19(k) ROP +/− 10 70:30 19(k) ROP −− 1 70:30 30(a) ROP ++ 10 70:3030(a) ROP ++ 48% 10 70:30 31(a) P8 46% 5 70:30 31(b) P8 32% 5 50:5031(c) P8 +/++ var 5 50:50 31(d) P8 12% 5 50:50 31(e) P8 24% 5 50:5032(a) P9 20% 5 50:50 33(b) ROP ++ 55% 10 70:30 33(b) ROP +/− 14% 1 70:3033(b) P6-P10 37% IP* 70:30 33(e) P8 22% 5 70:30 33(f) P8 20% 5 50:5035(a) P8  4% 5 50:50 35(aa) P8 − 5 50:50 35(c) P8  0% 5 50:50 35(cc) P8+/++ 5 50:50 35(dd) P8 ++/+++ var 5 50:50 35(ee) P8 +/++ 5 50:50 35(h)P8 +/− 5 50:50 35(i) P8 +/++ 5 50:50 35(j) P8 7% 5 50:50 35(k) P8 − 550:50 35(k) P8 ++ 5 50:50 35(v) P8 20% 5 50:50 38(a) ROP +++ 55% 1070:30 38(a) ROP + 16% 1 70:30 39(b) P8  9% 5 50:50 4(a) ROP ++ 10 70:3041(a) ROP +++ 64% 10 70:30 41(a) P8  0% 0.5 50:50 41(a) P8  4% 1 50:5041(a) P8 ++/+++ 5 50:50 41(c) ROP +++ 54% 10 70:30 41(c) ROP +/− 16% 170:30 41(c) P8 ++ 5 50:50 41(d) ROP +++ 59% 10 70:30 41(d) ROP +/−  0% 170:30 41(e) P8  8% 5 50:50 41(ee) P8 +/++ var 5 50:50 41(g) P8 37% 550:50 41(h) P8  0% 5 70:30 41(j) P8 +/++ 5 50:50 41(k) P8  1% 5 50:5041(l) P8 28% 2.5 70:30 41(m) P8 10% 5 50:50 41(mm) P8 + 5 50:50 41(n) P8 2% 5 50:50 41(o) P8  2% 5 50:50 41(p) P8 35% 5 50:50 41(r) P8 +/++ var5 50:50 42(a) ROP +++ 23% 10 70:30 42(a) ROP +  1% 1 70:30 42(a) ROP +10 70:30 42(a) P9 55% 10 70:30 42(a) P6-P10 61% IP* 70:30 42(a) P8 +/++5 50:50 42(b) P9 40% 10 70:30 42(c) P8 36% 5 50:50 45(b) ROP ++ 60% 1070:30 45(b) ROP +/− 25% 1 70:30 49(a) P8 54% 5 50:50 49(b) P8  5% 550:50 5(b) ROP ++ 45% 5 70:30 59(a) ROP 41% 10 0.5% CMC 59(a) ROP 19% 10.5% CMC 6(a) ROP ++ 5 65:35 6(b) ROP ++ 10 70:30

[1068] Phosphorylase Kinase

[1069] Phosphorylase Kinase Construct for Assay.

[1070] The truncated catalytic subunit (gamma subunit) of phosphorylasekinase (amino acids 1-298) was expressed in E.coli and isolated frominclusion bodies. Phosphorylase kinase was then refolded and stored inglycerol at −20° C.

[1071] Phosphorylase Kinase Assay. In the assay, the purified catalyticsubunit is used to phosphorylate phosphorylase b using radiolabled ATP.Briefly, 1.5 mg/ml of phosphorylase b is incubated with 10 nMphosphorylase kinase in 10 mM MgCl₂, 50 mM Hepes pH 7.4, at 37° C. Thereaction is started with the addition of ATP to 100 uM and incubated for15 min at 25° C. or 37° C. The reaction was terminated and proteins wereprecipitated by the addition of TCA to 10% final concentration. Theprecipitated proteins were isolated on a 96 well Millipore MADP NOBfilter plate. The filter plate was then extensively washed with 20% TCA,and dried. Scintilation fluid was then added to the plate andincorporated radiolabel was counted on a Wallac microbeta counter. The %inhibition of phosphoryl transfer from ATP to phosphorylase b in thepresence of 10 μM of compound is shown in the Table 8 below. TABLE 8Example # % Inhibition @ 10 μM 52(b) 92 27(f) 90 27(a) 37

[1072] The exemplary compounds described above may be formulated intopharmaceutical compositions according to the following general examples.

Example 1

[1073] Parenteral Composition

[1074] To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula I is dissolved in DMSO and then mixed with 10 mL of0.9% sterile saline. The mixture is incorporated into a dosage unit formsuitable for administration by injection.

Example 2

[1075] Oral Composition

[1076] To prepare a pharmaceutical composition for oral delivery, 100 mgof a compound of Formula I is mixed with 750 mg of lactose. The mixtureis incorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

Example 3

[1077] Intraocular Composition

[1078] To prepare a sustained-release pharmaceutical composition forintraocular delivery, a compound of Formula I is suspended in a neutral,isotonic solution of hyaluronic acid (1.5% conc.) in phosphate buffer(pH 7.4) to form a 1% suspension.

[1079] It is to be understood that the foregoing description isexemplary and explanatory in nature, and is intended to illustrate theinvention and its preferred embodiments. Through routineexperimentation, the artisan will recognize apparent modifications andvariations that may be made without departing from the spirit of theinvention. Thus, the invention is intended to be defined not by theabove description, but by the following claims and their equivalents.

What is claimed is:
 1. A compound of the Formula I:

wherein: R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³ where R³ is a substituted orunsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; and R² is a substituted or unsubstituted aryl, heteroaryl,or Y-X, where Y is O, S, C═CH₂, C═O, S═O, SO₂, alkylidene, NH, orN-(C₁-C₈ alkyl), and X is substituted or unsubstituted Ar, heteroaryl,NH-(alkyl), NH-(cycloalkyl), NH-(heterocycloalkyl), NH(aryl),NH(heteroaryl), NH-(alkoxyl), or NH-(dialkylamide), where Ar is aryl; ora pharmaceutically acceptable prodrug, pharmaceutically activemetabolite, or pharmaceutically acceptable salt thereof.
 2. A compoundof the Formula I(a):

wherein: R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; and R² is a substituted or unsubstituted aryl or Y-Ar, whereY is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₁-C₈ alkyl), andAr is a substituted or unsubstituted aryl; or a pharmaceuticallyacceptable prodrug, pharmaceutically active metabolite, orpharmaceutically acceptable salt thereof.
 3. A compound of the FormulaII:

wherein: R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;R⁴ and R⁷ are each independently hydrogen, OH, halo, C₁-C₈ alkyl, C₁-C₈alkoxy, C₁-C₈ alkenyl, aryloxy, thioaryl, CH₂—OH, CH₂—O— (C₁-C₈ alkyl),CH₂—O-aryl, CH₂—S-(C₁-C₈ alkyl), or CH₂—S-aryl; R⁵ and R⁶ are eachindependently hydrogen, OH, halo, Z-alkyl, Z-aryl, or Z-CH₂CH═CH₂, whereZ is O, S, NH, or CH₂, and the alkyl and aryl moiety of Z-alkyl andZ-aryl are each optionally substituted; or a pharmaceutically acceptableprodrug, pharmaceutically active metabolite, or pharmaceuticallyacceptable salt thereof.
 4. A compound, pharmaceutically acceptableprodrug, pharmaceutically active metabolite, or pharmaceuticallyacceptable salt according to claim 3, wherein: R¹ is a substituted orunsubstituted bicyclic heteroaryl, or a group of the formula CH═CH—R³where R³ is a substituted or unsubstituted aryl or heteroaryl; R⁴ and R⁷are each independently hydrogen or C₁-C₈ alkyl; and R⁵ and R⁶ are eachindependently halo, Z-alkyl, or Z-CH₂CH═CH₂, where Z is O or S and alkylis optionally substituted.
 5. A compound of the Formula III:

wherein: R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₂-C₈ alkyl); R⁸is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxyl, or aryloxyl; R¹⁰ isindependently selected from hydrogen, halogen, and lower-alkyl; or apharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt thereof.
 6. A compound,pharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt according to claim 5, wherein: R¹ isa substituted or unsubstituted bicyclic heteroaryl, or a group of theformula CH═CH—R³ where R³ is a substituted or unsubstituted aryl orheteroaryl; Y is O, S, C═CH₂, C═O, NH, or N—(C₂-C₈ alkyl); R⁸ is asubstituted or unsubstituted aryl or heteroaryl, alkyl, and alkenyl, andR¹⁰ is hydrogen or halogen.
 7. A compound of the Formula III(a):

wherein: R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₂-C₈ alkyl); R⁸is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxyl, or aryloxyl; or apharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt thereof.
 8. A compound,pharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt according to claim 7, wherein: R¹ isa substituted or unsubstituted bicyclic heteroaryl, or a group of theformula CH═CH—R³ where R³ is a substituted or unsubstituted aryl orheteroaryl; Y is O, S, C═CH₂, C═O, NH, or N-(C₁-C₈ alkyl); and R⁸ is asubstituted or unsubstituted aryl, heteroaryl, alkyl, or alkenyl.
 9. Acompound, pharmaceutically acceptable prodrug, pharmaceutically activemetabolite, or pharmaceutically acceptable salt according to claim 7,wherein: R¹ is CH═CH—R³, where R³ is a substituted or unsubstituted arylgroup; Y is O or S; and R⁸ is a substituted or unsubstituted aryl orheteroaryl.
 10. A compound of the Formula IV:

wherein: R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₁-C₈ alkyl); R⁹is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl, NH-(C₁-C₈ alkyl),NH-(aryl), NH-(heteroaryl), N═CH-alkyl), NH(C-O)R¹¹, or NH₂, where R¹¹is independently selected from hydrogen, substituted or unsubstitutedalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R¹⁰ isindependently selected from hydrogen, halogen, and lower-alkyl; or apharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt thereof.
 11. A compound,pharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt according to claim 10, wherein: R¹is a group of the formula CH═CH—R³ where R³ is a substituted orunsubstituted aryl or heteroaryl; Y is S or NH; and R⁹ is a substitutedor unsubstituted alkyl, alkoxyl, or NH-(heteroaryl).
 12. A compound,pharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt, selected from:


13. A pharmaceutical composition comprising: (a) a therapeuticallyeffective amount of a compound, pharmaceutically acceptable prodrug,pharmaceutically active metabolite, or pharmaceutically acceptable saltof claim 1; and (b) a pharmaceutically acceptable carrier, diluent, orvehicle therefor.
 14. A method of treating a mammalian disease conditionmediated by protein kinase activity, comprising administering to amammal in need thereof a therapeutically effective amount of a compound,pharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt as defined in claim
 1. 15. A methodaccording to claim 14, wherein the mammalian disease condition isassociated with tumor growth, cell proliferation, or angiogenesis.
 16. Amethod of modulating the activity of a protein kinase receptor,comprising contacting the kinase receptor with an effective amount of acompound, pharmaceutically acceptable prodrug, pharmaceutically activemetabolite, or pharmaceutically acceptable salt as defined in claim 1.17. A method according to claim 16, wherein the protein kinase receptoris a VEGF receptor.